Drug combinations comprising a DGAT inhibitor and a PPAR-agonist

ABSTRACT

The present invention relates to combinations of a DGAT inhibitor and a peroxisome proliferator-activator receptor (PPAR) agonist or a prodrug thereof. The invention further relates to methods for preparing such combinations, pharmaceutical compositions comprising said combinations as well as the use as a medicament of said combinations. 
     The present invention also relates to novel DGAT inhibitors. The invention further relates to methods for preparing such compounds, pharmaceutical compositions comprising said compounds as well as the use as a medicament of said compounds.

CROSS REFERENCE TO RELATED APPLICATIONS

This application a continuation application of U.S. patent application Ser. No. 12/993,491, filed Nov. 19, 2010, currently pending, the disclosure of which is hereby incorporated by reference, which is the U.S. national stage of Application No. PCT/EP2009/056800, filed Jun. 3, 2009, which application claims priority from PCT/EP2008/057060, filed Jun. 6, 2008; PCT/EP2008/057008, filed Jun. 5, 2008;PCT/EP/056983, filed Jun. 5, 2008; PCT/EP2008/057011, filed Jun. 5, 2008 and EP 08170780.4, filed Dec. 5, 2008.

FIELD OF THE INVENTION

This invention concerns novel drug combinations comprising an acyl CoA:diacylglycerol acyltransferase (DGAT) inhibitor, in particular a DGAT1 inhibitor, and a peroxisome proliferator-activated receptor (PPAR) agonist, in particular a PPAR-α agonist, pharmaceutical compositions comprising said novel drug combinations as active ingredients, as well as the use of said combinations as a medicament and for the manufacture of a medicament.

The present invention also concerns new piperidine/piperazine derivatives having DGAT inhibitory activity, in particular DGAT1 inhibitory activity. The invention further relates to methods for their preparation and pharmaceutical compositions comprising them. The invention also relates to the use of said compounds for the manufacture of a medicament for the prevention or the treatment of a disease mediated by DGAT, in particular DGAT 1.

BACKGROUND OF THE INVENTION

Triglycerides represent the major form of energy stored in eukaryotes. Disorders or imbalances in triglyceride metabolism are implicated in the pathogenesis of and increased risk for obesity, insulin resistance syndrome and type II diabetes, nonalcoholic fatty liver disease and coronary heart disease (see, Lewis, et al, Endocrine Reviews (2002) 23:201 and Malloy and Kane, Adv. Intern. Med. (2001) 47:11 1). Additionally, hypertriglyceridemia is often an adverse consequence of cancer therapy (see, Bast, et al. Cancer Medicament, 5th Ed., (2000) B.C. Decker, Hamilton, Ontario, Calif.).

A key enzyme in the synthesis of triglycerides is acyl CoA:diacylglycerol acyltransferase, or DGAT. DGAT is a microsomal enzyme that is widely expressed in mammalian tissues and that catalyzes the joining of 1,2-diacylglycerol (DAG) and fatty acyl CoA to form triglycerides (TG) at the endoplasmic reticulum (reviewed in Chen and Farese, Trends Cardiovasc. Med. (2000) 10: 188 and Farese, et al, Curr. Opin. Lipidol. (2000) 11:229). It was originally thought that DGAT uniquely controlled the catalysis of the final step of acylation of diacylglycerol to triglyceride in the two major pathways for triglyceride synthesis, the glycerol phosphate and monoacylglycerol pathways. Because triglycerides are considered essential for survival, and their synthesis was thought to occur through a single mechanism, inhibition of triglyceride synthesis through inhibiting the activity of DGAT has been largely unexplored.

Genes encoding mouse DGAT1 and the related human homologs ARGP1 (human DGAT1) and ARGP2 (human ACAT2) now have been cloned and characterized (Cases, et al, Pro.c Nat.l Acad. Sci. (1998) 95:13018; Oelkers, et al, J. Biol. Chem. (1998) 273:26765). The gene for mouse DGAT1 has been used to create DGAT knock-out mice to better elucidate the function of the DGAT gene.

Unexpectedly, mice unable to express a functional DGAT1 enzyme (Dgat1−/− mice) are viable and still able to synthesize triglycerides, indicating that multiple catalytic mechanisms contribute to triglyceride synthesis (Smith, et al, Nature Genetics (2000) 25:87). Other enzymes that catalyze triglyceride synthesis, for example, DGAT2 and diacylglycerol transacylase, also have been identified (Cases, et al, J. Biol. Chem. (2001) 276:38870). Gene knockout studies in mice have revealed that DGAT2 plays a fundamental role in mammalian triglyceride synthesis and is required for survival. DGAT2 deficient mice are lipopenic and die soon after birth, apparently from profound reductions in substrates for energy metabolism and from impaired permeability barrier function in the skin. (Farese, et al., J. Biol. Chem. (2004) 279: 11767).

Significantly, Dgat1−/− mice are resistant to diet-induced obesity and remain lean. Even when fed a high fat diet (21% fat) Dgat1−/− mice maintain weights comparable to mice fed a regular diet (4% fat) and have lower total body triglyceride levels. The obesity resistance in Dgat1−/− mice is not due to decreased caloric intake, but the result of increased energy expenditure and decreased resistance to insulin and leptin (Smith, et al, Nature Genetics (2000) 25:87; Chen and Farese, Trends Cardiovasc. Med. (2000) 10: 188; and Chen, et al, J. Clin. Invest. (2002) 109:1049). Additionally, Dgat1−/− mice have reduced rates of triglyceride absorption (Buhman, et al, J. Biol. Chem. (2002) 277:25474). In addition to improved triglyceride metabolism, Dgat1−/− mice also have improved glucose metabolism, with lower glucose and insulin levels following a glucose load, in comparison to wild-type mice (Chen and Farese, Trends Cardiovasc. Med. (2000) 10: 188).

The finding that multiple enzymes contribute to catalyzing the synthesis of triglyceride from diacylglycerol is significant, because it presents the opportunity to modulate one catalytic mechanism of this biochemical reaction to achieve therapeutic results in an individual with minimal adverse side effects. Compounds that inhibit the conversion of diacylglycerol to triglyceride, for instance by specifically inhibiting the activity of DGAT1, will find use in lowering corporeal concentrations and absorption of triglycerides to therapeutically counteract the pathogenic effects caused by abnormal metabolism of triglycerides in obesity, insulin resistance syndrome and overt type II diabetes, congestive heart failure and atherosclerosis, and as a consequence of cancer therapy.

Because of the ever increasing prevalence of obesity, type II diabetes, heart disease and cancer in societies throughout the world, there is a pressing need in developing new therapies to effectively treat and prevent these diseases. Therefore there is an interest in developing compounds that can potently and specifically inhibit the catalytic activity of DGAT, in particular DGAT1.

We have now unexpectedly found that novel compounds exhibiting DGAT inhibitory activity, in particular DGAT1 inhibitory activity, and these compounds can therefore be used to prevent or treat a disease associated with or mediated by DGAT, such as for example obesity, type II diabetes, heart disease and cancer. The compounds of the invention differ from the prior art compounds in structure, in their pharmacological activity, pharmacological potency, and/or pharmacological profile.

We have also unexpectedly found that DGAT inhibitors, including the DGAT inhibitors of the present invention, can be used to elevate the levels of one or more satiety hormones, in particular glucagon-like-peptide-1 (GLP-1) and therefore DGAT inhibitors, in particular DGAT1 inhibitors, can also be used to prevent or treat a disease which can benefit from elevated levels of a satiety hormone, in particular GLP-1. Glucagon-like peptide 1 (GLP-1) is an intestinal hormone which generally stimulates insulin secretion during hyperglycemia, suppresses glucagon secretion, stimulates (pro) insulin biosynthesis and decelerates gastric emptying and acid secretion. GLP-1 is secreted from L cells in the small and large bowel following the ingestion of fat and proteins. GLP-1 has been suggested, among other indications, as a possible therapeutic agent for the management of type II non-insulin-dependent diabetes mellitus as well as related metabolic disorders, such as obesity.

The present novel compounds make it possible to treat a disease which can benefit from elevated levels of GLP-1 with small molecules (compared to large molecules such as proteins or protein-like compounds, e.g. GLP-1 analogues).

The peroxisome proliferator-activated receptors (PPAR) belong to the steroid hormone nuclear receptor superfamily of ligand-activated transcription factors that mediate the specific effects of small lipophilic compounds, such as steroids, retinoids and fatty acids, on DNA transcription. They play an important role in the regulation of lipid metabolism, in the regulation of energy homeostasis, inflammation, artherosclerosis and glucose control. Three subtypes are identified so far, namely PPAR-α, PPAR-β/δ and PPAR-γ. The three isoforms exhibit different tissue distribution as well as different ligand specificities.

PPAR-α plays a crucial role in the intracellular lipid metabolism. The PPAR-α subtype is mainly expressed in tissues with elevated mitochondrial and peroxisomal fatty acid β-oxidation rates, that efficiently harvest energy from lipids, including liver, skeletal muscle, heart muscle, proximal tubular epithelial cells of the kidney, and brown fat (brown adipose tissue). PPAR-α is also present in cells of the arterial wall, in monocytes/macrophages, smooth muscle cells, endothelial cells, in hepatocytes, and in cardiac myocytes.

Saturated and unsaturated fatty acids are found to be the primary natural PPAR-α ligands. In general, PPAR-α can be activated by a heterogeneous group of compounds, which include natural and synthetic agonists, such as eicosanoids, leukotriene β₄, carbaprostacyclin, nonsteroidal anti-inflammatory drugs, pirinixic acid (WY-14643; PPAR-α/γ agonist), phthalate ester plasticizers, pterostilbene, fibrates or active metabolites thereof, α-substituted phenyl-propanoic acid derivatives and isoxazolyl-serine-based compounds. Finally, PPAR-α is induced by glucocorticoids in response to stress and follows a diurnal rhythm.

Fibrates or active metabolites thereof such as fibric acid derivatives, are PPAR-α agonists, and have been used to treat dyslipidemia for several decades because of their triglyceride lowering and high-density lipoprotein (HDL) cholesterol elevating effects. Fibric acid derivatives lower the levels of triglyceride-rich lipoproteins, such as very low-density lipoproteins (VLDL), raise HDL levels, and have variable effect on low-density lipoproteins (LDL) levels. The effects on VLDL levels appear to result primarily from an increase in lipoprotein lipase activity, especially in muscle. This leads to enhanced hydrolysis of VLDL triglyceride content and an enhanced VLDL catabolism. Fibric acid agents also may alter the composition of the VLDL, for example, by decreasing hepatic production of apoC-III, an inhibitor of lipoprotein lipase activity. These compounds are also reported to decrease hepatic VLDL triglyceride synthesis, possibly by inhibiting fatty acid synthesis and by promoting fatty acid oxidation. In addition, they have been documented to be beneficial in the prevention of ischemic heart disease in individuals with dyslipidemia and they can also modestly decrease elevated fibrinogen and PAI-1 levels. Well-known examples of fibrates are fenofibrate (fenofibric acid as active metabolite), ABT-335 (which is the choline salt of fenofibric acid), bezafibrate, clofibrate, ciprofibrate, etofibrate, pirifibrate, beclofibrate and gemfibrozil (PPAR-α modulator).

Because of the ever increasing prevalence of obesity, type II diabetes, heart disease and cancer in societies throughout the world, there is a pressing need in developing new therapies to effectively treat and prevent these diseases.

We have now unexpectedly found that the combination of a compound showing DGAT inhibitory activity, in particular DGAT1 inhibitory activity, with a PPAR agonist, in particular a PPAR-α agonist, may exhibit an increased and/or accelerated effect on weight loss, compared to the effect of the DGAT inhibitor or the PPAR agonist each separately, and additional can decrease food intake. The combinations of the present invention may show synergy compared to administration of the composing ingredients alone.

BACKGROUND PRIOR ART

WO 2006/034441 discloses heterocyclic derivatives and their use as stearoyl CoA desaturase inhibitors (SCD-1 inhibitors).

WO 2006/086445 relates to a combination therapy of a SCD-1 inhibitor and another drug to treat adverse weight gain.

WO 2006/004200 and JP2007131584 relate to urea and amino derivatives having DGAT inhibitory activity.

WO 2004/047755 relates to fused bicyclic nitrogen-containing heterocycles having DGAT inhibitory activity.

WO2005/072740 relates to an anorectic action of a compound having DGAT inhibitory activity.

WO 2007/071966 discloses a conjoint treatment of pyrimido-[4,5-B]-oxazines showing DGAT inhibitory activity together with anti-dyslipidaemia agents such as PPAR-α agonists.

WO2008/148851, WO2008/148840, WO2008/148849 and WO2008/148868 concern piperidine/piperazine derivatives having DGAT inhibitory activity.

DESCRIPTION OF THE DRAWINGS

FIG. 1A shows the food intake of mice treated with a DGAT inhibitor (compound 223 of Class D—called D in FIG. 1A), fenofibrate (F) or both, compared to the control group. ‘BL’ means baseline food intake.

FIG. 1B shows the food intake of DIO C57BL/6 mice fed with a high-fat diet containing fenofibrate (F) and compound 223 of Class D (D).

FIG. 1C shows the high fat diet intake (g) of DIO C57BL/6 mice treated with a DGAT inhibitor (compound 358 of Class D), fenofibrate (F) or both, compared to the control group.

FIG. 1D shows food intake of lean C57BL/6 mice fed a low-fat diet containing compound 223 of Class D (D) and fenofibrate (F).

FIG. 2A shows the change in body weight (g) of DIO C57BL/6 mice treated with a DGAT inhibitor (compound 223 of Class D—25 mpk/d), fenofibrate (31 mpk/d) or both.

FIG. 2B shows the body weight change of DIO C57BL/6 mice fed with a high-fat diet containing fenofibrate (F) and compound 223 of Class D (D).

FIG. 2C shows the change in body weight (g) of DIO C57BL/6 mice fed with a high-fat diet containing DGAT inhibitor (compound 358 of Class D), fenofibrate or both.

FIG. 2D shows food intake of lean C57BL/6 mice fed a high-fat diet containing compound 223 of Class D (D) and fenofibrate (F).

FIG. 3A shows food intake on day 1 of DIO C57BL/6 mice fed with a high-fat diet containing compound 223 of Class D and fenofibrate (D+F).

FIG. 3B shows day-1 food intake of mice fed a low and high-fat diet containing 0.01/0.0125% w/w compound 223 of Class D/fenofibrate (D/F). DIO C57BL/6 mice were acclimated to cages designed for measuring food intake. After adaptation to either a low-fat (10 kcal % fat) or high-fat (45 kcal % fat) diet, mice were switched to a diet with the same fat content (10 kcal % and 45 kcal % fat respectively), but supplemented with 0.01/0.0125% w/w D/F.

DESCRIPTION OF THE INVENTION

The present invention relates to combinations of a DGAT inhibitor and a peroxisome proliferator-activator receptor (PPAR) agonist or a prodrug thereof.

In an embodiment, the present invention relates to combinations of a DGAT inhibitor and a PPAR-α agonist or a prodrug thereof.

In an embodiment, the present invention relates to combinations of a DGAT1 inhibitor and a PPAR agonist or a prodrug thereof.

In an embodiment, the present invention relates to combinations of a DGAT1 inhibitor and a PPAR-α agonist or a prodrug thereof.

In an embodiment, the present invention relates to combinations of a DGAT inhibitor, in particular a DGAT1 inhibitor, and a PPAR-α agonist or a prodrug thereof selected from the group of fibrates.

In an embodiment, the present invention relates to combinations of a DGAT inhibitor, in particular a DGAT1 inhibitor, and fenofibrate.

In an embodiment, the present invention relates to combinations of a PPAR agonist or a prodrug thereof and a DGAT inhibitor wherein the DGAT inhibitor is selected from

-   a) a compound having the formula

-   including any stereochemically isomeric form thereof, wherein -   A represents CH or N; -   X represents O or NR^(x); -   the dotted line represents an optional bond in case A represents a     carbon atom; -   Y represents a direct bond; —NR^(x)—C(═O)—; —C(═O)—NR^(x)—;     —NR^(x)—C(═O)—Z—; —NR^(x)—C(═O)—Z—NR^(y)—;     —NR^(x)—C(═O)—Z—NR^(y)—C(═O)—; —NR^(x)—C(═O)—Z—NR^(y)—C(═O)—O—;     —NR^(x)—C(═O)—Z—O—; —NR^(x)—C(═O)—Z—O—C(═O)—;     —NR^(x)—C(═O)—Z—C(═O)—; —NR^(x)—C(═O)—Z—C(═O)—O—;     —NR^(x)—C(═O)—O—Z—C(═O)—; —NR^(x)—C(═O)—O—Z—C(═O)—O—;     —NR^(x)—C(═O)—O—Z—O—C(═O)—; —NR^(x)—C(═O)—Z—C(═O)—NR^(y)—;     —NR^(x)—C(═O)—Z—NR^(y)—C(═O)—NR^(y)—; —C(═O)—Z—; —C(═O)—Z—O—;     —C(═O)—NR^(x)—Z—; —C(═O)—NR^(x)—Z—O—; —C(═O)—NR^(x)—Z—C(═O)—O—;     —C(═O)—NR^(x)—Z—O—C(═O)—; —C(═O)—NR^(x)—O—Z—;     —C(═O)—NR^(x)—Z—NR^(y)—; —C(═O)—NR^(x)—Z—NR^(y)—C(═O)—;     —C(═O)—NR^(x)—Z—NR^(y)—C(═O)—O—; -   Z represents a bivalent radical selected from C₁₋₆alkanediyl,     C₂₋₆alkenediyl or C₂₋₆ alkynediyl; wherein each of said     C₁₋₆alkanediyl, C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally be     substituted with C₁₋₄alkyloxy, C₁₋₄alkylthio, hydroxyl, cyano or     aryl; and wherein two hydrogen atoms attached to the same carbon     atom in the definition of Z may optionally be replaced by     C₁₋₆alkanediyl; -   R^(x) represents hydrogen or C₁₋₄alkyl; -   R^(y) represents hydrogen; C₁₋₄alkyl optionally substituted with     C₃₋₆cycloalkyl or aryl or Het; C₂₋₄alkenyl; or —S(═O)_(p)-aryl; -   R¹ represents C₁₋₁₂alkyl optionally substituted with cyano,     C₁₋₄alkyloxy, C₁₋₄alkyl-oxyC₁₋₄alkyloxy, C₃₋₆cycloalkyl or aryl;     C₂₋₆alkenyl; C₂₋₆alkynyl; C₃₋₆cycloalkyl; aryl¹; aryl¹C₁₋₆alkyl;     Het¹; or Het¹C₁₋₆alkyl; provided that when Y represents     —NR^(x)—C(═O)—Z—; —NR^(x)—C(═O)—Z—NR^(y);     —NR^(x)—C(═O)—Z—C(═O)—NR^(y)—; —C(═O)—Z—;     —NR^(x)—C(═O)—Z—NR^(y)—C(═O)—NR^(y)—; —C(═O)—NR^(x)—Z—;     —C(═O)—NR^(x)—O—Z—; or —C(═O)—NR^(x)—Z—NR^(y)—; then R¹ may also     represent hydrogen; -   R² and R³ each independently represent hydrogen; hydroxyl; carboxyl;     halo; C₁₋₆alkyl; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally     substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;     C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl; mono-or     di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-or     di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; -   R⁴ represents hydrogen; hydroxyl; carboxyl; halo; C₁₋₆alkyl;     polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with     C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy;     C₁₋₆alkyloxycarbonyl wherein C₁₋₆alkyl may optionally be substituted     with aryl; cyano; C₁₋₆alkylcarbonyl; nitro; amino; mono-or     di(C₁₋₄alkyl)amino; C₁₋₄alkylcarbonylamino; —S(═O)_(p)—C₁₋₄alkyl;     R⁶R⁵N—C(═O)—; R⁶R⁵N—C₁₋₆alkyl; C₃₋₆cycloalkyl; aryl; aryloxy;     arylC₁₋₄alkyl; aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl;     Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—; -   R⁵ represents hydrogen; C₁₋₄alkyl optionally substituted with     hydroxyl or C₁₋₄alkyloxy; R⁸R⁷N—C₁₋₄alkyl; C₁₋₄alkyloxy; Het; aryl;     R⁸R⁷N—C(═O)—C₁₋₄alkyl; -   R⁶ represents hydrogen or C₁₋₄alkyl; -   R⁷ represents hydrogen; C₁₋₄alkyl; C₁₋₄alkylcarbonyl; -   R⁸ represents hydrogen or C₁₋₄alkyl; or -   R⁷ and R⁸ may be taken together with the nitrogen to which they are     attached to form a saturated monocyclic 5, 6 or 7-membered     heterocycle which may further contain one or more heteroatoms each     independently selected from O, S, S(═O)_(p) or N; and which     heterocycle may optionally be substituted with C₁₋₄alkyl; -   R⁹ represents hydrogen, halo, C₁₋₄alkyl, C₁₋₄alkyl substituted with     hydroxyl; -   aryl represents phenyl or phenyl substituted with at least one     substituent, in particular one, two, three, four or five     substituents, each substituent independently being selected from     hydroxyl; carboxyl; halo; C₁₋₆alkyl optionally substituted with     C₁₋₄alkyloxy, amino or mono-or di(C₁₋₄alkyl)amino;     polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with     C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;     C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl; mono-or     di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-or     di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; -   aryl¹ represents phenyl, naphthalenyl or fluorenyl; each of said     phenyl, naphthalenyl or fluorenyl optionally substituted with at     least one substituent, in particular one, two, three, four or five     substituents, each substituent independently being selected from     hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl optionally substituted with     carboxyl, C₁₋₄alkyloxycarbonyl or aryl-C(═O)—; hydroxyC₁₋₆alkyl     optionally substituted with aryl or aryl-C(═O)—; polyhaloC₁₋₆alkyl;     C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy;     C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonyl wherein     C₁₋₆alkyl may optionally be substituted with aryl; cyano;     aminocarbonyl; mono-or di(C₁₋₄alkyl)aminocarbonyl;     C₁₋₆alkylcarbonyl; amino; mono-or di(C₁₋₆alkyl)amino;     R⁶R⁵N—C₁₋₆alkyl; C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—; Het-NR^(x)—;     C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;     HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl;     C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;     arylC₁₋₄alkyl; aryl-C(═O)—; aryl-C(═O)—C₁₋₄alkyl; Het; HetC₁₋₄alkyl;     Het-C(═O)—; Het-C(═O)—C₁₋₄alkyl; Het-O—; -   Het represents a monocyclic non-aromatic or aromatic heterocycle     containing at least one heteroatom each independently selected from     O, S, S(═O)_(p) or N; or a bicyclic or tricyclic non-aromatic or     aromatic heterocycle containing at least one heteroatom each     independently selected from O, S, S(═O)_(p) or N; said monocyclic     heterocycle or said bi-or tricyclic heterocycle optionally being     substituted with at least one substituent, in particular one, two,     three, four or five substituents, each substituent independently     being selected from hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl     optionally substituted with C₁₋₄alkyloxy, amino or mono-or     di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally     substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;     C₁₋₆alkyl-oxycarbonyl; cyano; aminocarbonyl; mono-or     di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-or     di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; -   Het¹ represents a monocyclic non-aromatic or aromatic heterocycle     containing at least one heteroatom each independently selected from     O, S, S(═O)_(p) or N; or a bicyclic or tricyclic non-aromatic or     aromatic heterocycle containing at least one heteroatom each     independently selected from O, S, S(═O)_(p) or N; said monocyclic     heterocycle or said bi-or tricyclic heterocycle optionally being     substituted with at least one substituent, in particular one, two,     three, four or five substituents, each substituent independently     being selected from hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl     optionally substituted with carboxyl, C₁₋₄alkyloxycarbonyl or     aryl-C(═O)—; hydroxyC₁₋₆alkyl optionally substituted with aryl or     aryl-C(═O)—; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted     with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;     C₁₋₆alkyloxy-carbonyl wherein C₁₋₆alkyl may optionally be     substituted with aryl; cyano; aminocarbonyl; mono-or     di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; amino; mono-or     di(C₁₋₆alkyl)amino; R⁶R⁵N—C₁₋₆alkyl; C₃₋₆cycloalkyl-NR^(x)—;     aryl-NR^(x)—; Het-NR^(x)—; C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—;     arylC₁₋₄alkyl-NR^(x)—; HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl;     C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—;     aryl; aryloxy; arylC₁₋₄alkyl; aryl-C(═O)—; aryl-C(═O)—C₁₋₄alkyl;     Het; HetC₁₋₄alkyl; Het-C(═O)—; Het-C(═O)—C₁₋₄alkyl; Het-O—; -   p represents 1 or 2; -   a N-oxide thereof, a pharmaceutically acceptable salt thereof or a     solvate thereof; -   b) a compound having the formula

-   including any stereochemically isomeric form thereof, wherein -   A represents CH or N; -   the dotted line represents an optional bond in case A represents a     carbon atom; -   X represents —NR^(x)—C(═O)—; —Z—C(═O)—; —Z—NR^(x)—C(═O)—; —S(═O)p-;     C(═S)—; —NR^(x)—C(═S)—; —Z—C(═S)—; —Z—NR^(x)—C(═S)—; —O—C(═O)—;     —C(═O)—C(═O)—; -   Z represents a bivalent radical selected from C₁₋₆alkanediyl,     C₂₋₆alkenediyl or C₂₋₆alkynediyl; wherein each of said     C₁₋₆alkanediyl, C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally be     substituted with hydroxyl or amino; and wherein two hydrogen atoms     attached to the same carbon atom in C₁₋₆alkanediyl may optionally be     replaced by C₁₋₆alkanediyl; -   R^(x) represents hydrogen or C₁₋₄alkyl; -   R¹ represents a 5-membered monocyclic heterocycle containing at     least 2 heteroatoms; a 6-membered aromatic monocyclic heterocycle;     or a 5-membered heterocycle containing at least 2 heteroatoms fused     with phenyl, cyclohexyl or a 5-or 6-membered heterocycle; wherein     each of said heterocycles may optionally be substituted with at     least one substituent, in particular one, two, three, four or five     substituents, each substituent independently being selected from     hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl optionally substituted with     carboxyl, C₁₋₄alkyloxycarbonyl or aryl-C(═O)—; hydroxyC₁₋₆alkyl     optionally substituted with aryl or aryl-C(═O)—; polyhaloC₁₋₆alkyl;     C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy;     C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonyl wherein     C₁₋₆alkyl may optionally be substituted with aryl; cyano;     aminocarbonyl; mono-or di(C₁₋₄alkyl)-aminocarbonyl;     C₁₋₆alkylcarbonyl; amino; mono-or di(C₁₋₆alkyl)amino;     R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—; Het-NR^(x)—;     C₃₋₆cycloalkyl-C₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;     HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl;     C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;     arylC₁₋₄alkyl; aryl-C(═O)—; aryl-C(═O)—C₁₋₄alkyl; Het; HetC₁₋₄alkyl;     Het-C(═O)—; Het-C(═O)—C₁₋₄alkyl; Het-O—; -   R² represents R³; -   R³ represents C₃₋₆cycloalkyl, phenyl, naphtalenyl,     2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl,     2,3-dihydrobenzofuranyl or a 6-membered aromatic heterocycle     containing 1 or 2 N atoms, wherein said C₃₋₆cycloalkyl, phenyl,     naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl,     2,3-dihydrobenzofuranyl or 6-membered aromatic heterocycle may     optionally be substituted with at least one substituent, in     particular one, two, three, four or five substituents, each     substituent independently selected from hydroxyl; carboxyl; halo;     C₁₋₆alkyl optionally substituted with hydroxy; polyhaloC₁₋₆alkyl;     C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy;     C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl wherein     C₁₋₆alkyl may optionally be substituted with aryl; cyano;     C₁₋₆alkylcarbonyl; nitro; amino; mono-or di(C₁₋₄alkyl)amino;     C₁₋₄alkylcarbonylamino; —S(═O)_(p)—C₁₋₄alkyl; R⁵R⁴N—C(═O)—;     R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl;     C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy; arylC₁₋₄alkyl;     aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl;     Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—; -   R⁴ represents hydrogen; C₁₋₄alkyl optionally substituted with     hydroxyl or C₁₋₄alkyloxy; R⁷R⁶N—C₁₋₄alkyl; C₁₋₄alkyloxy; Het; aryl;     R⁷R⁶N—C(═O)—C₁₋₄alkyl; -   R⁵ represents hydrogen or C₁₋₄alkyl; -   R⁶ represents hydrogen; C₁₋₄alkyl; C₁₋₄alkylcarbonyl; -   R⁷ represents hydrogen or C₁₋₄alkyl; or -   R⁶ and R⁷ may be taken together with the nitrogen to which they are     attached to form a saturated monocyclic 5, 6 or 7-membered     heterocycle which may further contain one or more heteroatoms     selected from O, S, S(═O)_(p) or N; and which heterocycle may     optionally be substituted with C₁₋₄alkyl; -   R⁸ represents hydrogen, halo, C₁₋₄alkyl, C₁₋₄alkyl substituted with     hydroxyl; -   aryl represents phenyl or phenyl substituted with at least one     substituent, in particular one, two, three, four or five     substituents, each substituent independently being selected from     hydroxyl; carboxyl; halo; C₁₋₆alkyl optionally substituted with     C₁₋₄alkyloxy, amino or mono-or di(C₁₋₄alkyl)amino;     polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with     C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;     C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl; mono-or     di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-or     di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; -   Het represents a monocyclic non-aromatic or aromatic heterocycle     containing at least one heteroatom selected from O, S, S(═O)_(p) or     N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle     containing at least one heteroatom selected from O, S, S(═O)_(p) or     N; said monocyclic heterocycle or said bi-or tricyclic heterocycle     optionally being substituted with at least one substituent, in     particular one, two, three, four or five substituents, each     substituent independently being selected from hydroxyl; oxo;     carboxyl; halo; C₁₋₆alkyl optionally substituted with C₁₋₄alkyloxy,     amino or mono-or di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy     optionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio;     polyhaloC₁₋₆alkyloxy; C₁₋₆alkyl-oxycarbonyl; cyano; aminocarbonyl;     mono-or di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino;     mono-or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl -   p represents 1 or 2; -   a N-oxide thereof, a pharmaceutically acceptable salt thereof or a     solvate thereof; -   c) a compound having the formula

-   including any stereochemically isomeric form thereof, wherein -   A represents CH or N; -   the dotted line represents an optional bond in case A represents a     carbon atom; -   X represents —O—C(═O)—; —C(═O)—C(═O)—; —NR^(x)—C(═O)—; —Z—C(═O)—;     —Z—NR^(x)—C(═O)—; —C(═O)—Z—; —NR^(x)—C(═O)—Z—; C(═S)—; —S(═O)p-;     —NR^(x)—C(═S)—; —Z—C(═S)—; —Z—NR^(x)—C(═S)—; —C(═S)—Z—;     —NR^(x)—C(═S)—Z—; -   Z represents a bivalent radical selected from C₁₋₆alkanediyl,     C₂₋₆alkenediyl or C₂₋₆alkynediyl; wherein each of said     C₁₋₆alkanediyl, C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally be     substituted with hydroxyl or amino; and wherein two hydrogen atoms     attached to the same carbon atom in C₁₋₆alkanediyl may optionally be     replaced by C₁₋₆alkanediyl; -   R^(x) represents hydrogen or C₁₋₄alkyl; -   Y represents —C(═O)—NR^(x)— or NR^(x)—C(═O)—; -   R¹ represents adamantanyl, C₃₋₆cycloalkyl; aryl¹ or Het¹; -   R² represents hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₃₋₆cycloalkyl,     phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl,     1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl or a 6-membered aromatic     heterocycle containing 1 or 2 N atoms, wherein said C₃₋₆cycloalkyl,     phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl,     1,3-benzodioxolyl or 6-membered aromatic heterocycle containing 1 or     2 N atoms may optionally be substituted with at least one     substituent, in particular one, two, three, four or five     substituents, each substituent independently selected from hydroxyl;     carboxyl; halo; C₁₋₆alkyl optionally substituted with hydroxy;     polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with     C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy;     C₁₋₆alkyloxycarbonyl wherein C₁₋₆alkyl may optionally be substituted     with aryl; cyano; C₁₋₆alkylcarbonyl; nitro; amino; mono-or     di(C₁₋₄alkyl)amino; C₁₋₄alkylcarbonylamino; —S(═O)_(p)—C₁₋₄alkyl;     R⁴R³N—C(═O)—; R⁴R³N—C₁₋₆alkyl; C₃₋₆cycloalkyl;     C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;     arylC₁₋₄alkyl; aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl;     Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—; -   R³ represents hydrogen; C₁₋₄alkyl optionally substituted with     hydroxyl or C₁₋₄alkyloxy; R⁶R⁵N—C₁₋₄alkyl; C₁₋₄alkyloxy; Het;     Het-C₁₋₄alkyl; aryl; R⁶R⁵N—C(═O)—C₁₋₄alkyl; -   R⁴ represents hydrogen or C₁₋₄alkyl; -   R⁵ represents hydrogen; C₁₋₄alkyl; C₁₋₄alkylcarbonyl; -   R⁶ represents hydrogen or C₁₋₄alkyl; or -   R⁵ and R⁶ may be taken together with the nitrogen to which they are     attached to form a saturated monocyclic 5, 6 or 7-membered     heterocycle which may further contain one or more heteroatoms each     independently selected from O, S, S(═O)_(p) or N; and which     heterocycle may optionally be substituted with C₁₋₄alkyl; -   R⁷ represents hydrogen, halo, C₁₋₄alkyl, C₁₋₄alkyl substituted with     hydroxyl; -   aryl represents phenyl or phenyl substituted with at least one     substituent, in particular one, two, three, four or five     substituents, each substituent independently being selected from     hydroxyl; carboxyl; halo; C₁₋₆alkyl optionally substituted with     C₁₋₄alkyloxy, amino or mono-or di(C₁₋₄alkyl)amino;     polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with     C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;     C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl; mono-or     di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-or     di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; -   aryl¹ represents phenyl, naphthalenyl or fluorenyl; each of said     phenyl, naphthalenyl or fluorenyl optionally substituted with at     least one substituent, in particular one, two, three, four or five     substituents, each substituent independently being selected from     hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl optionally substituted with     carboxyl, C₁₋₄alkyloxycarbonyl or aryl-C(═O)—; hydroxyC₁₋₆alkyl     optionally substituted with aryl or aryl-C(═O)—; polyhaloC₁₋₆alkyl;     C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy;     C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonyl wherein     C₁₋₆alkyl may optionally be substituted with aryl; cyano;     aminocarbonyl; mono-or di(C₁₋₄alkyl)aminocarbonyl;     C₁₋₆alkylcarbonyl; nitro; amino; mono-or di(C₁₋₆alkyl)amino;     R⁴R³N—C₁₋₆alkyl; C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—; Het-NR^(x)—;     C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;     HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl;     C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;     arylC₁₋₄alkyl; aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl;     Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—; -   Het represents a monocyclic non-aromatic or aromatic heterocycle     containing at least one heteroatom each independently selected from     O, S, S(═O)_(p) or N; or a bicyclic or tricyclic non-aromatic or     aromatic heterocycle containing at least one heteroatom each     independently selected from O, S, S(═O)_(p) or N; said monocyclic     heterocycle or said bi-or tricyclic heterocycle optionally being     substituted with at least one substituent, in particular one, two,     three, four or five substituents, each substituent independently     being selected from hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl     optionally substituted with C₁₋₄alkyloxy, amino or mono-or     di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally     substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;     C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl; mono-or     di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-or     di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; -   Het¹ represents a monocyclic non-aromatic or aromatic heterocycle     containing at least one heteroatom each independently selected from     O, S, S(═O)_(p) or N; or a bicyclic or tricyclic non-aromatic or     aromatic heterocycle containing at least one heteroatom each     independently selected from O, S, S(═O)_(p) or N; said monocyclic     heterocycle or said bi-or tricyclic heterocycle optionally being     substituted with at least one substituent, in particular one, two,     three, four or five substituents, each substituent independently     being selected from hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl     optionally substituted with aryl-C(═O)—; hydroxyC₁₋₆alkyl optionally     substituted with aryl or aryl-C(═O)—; polyhaloC₁₋₆alkyl;     C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy;     C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonyl wherein     C₁₋₆alkyl may optionally be substituted with aryl; cyano;     aminocarbonyl; mono-or di(C₁₋₄alkyl)aminocarbonyl;     C₁₋₆alkylcarbonyl; nitro; amino; mono-or di(C₁₋₆alkyl)amino;     R⁴R³N—C₁₋₆alkyl; C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—; Het-NR^(x)—;     C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;     HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl;     C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;     arylC₁₋₄alkyl; aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl;     Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—; -   p represents 1 or 2; -   a N-oxide thereof, a pharmaceutically acceptable salt thereof or a     solvate thereof; -   or -   d) a compound having the formula

-   including any stereochemically isomeric form thereof, wherein -   A represents CH or N; -   the dotted line represents an optional bond in case A represents a     carbon atom; -   X represents —C(═O)—; —O—C(═O)—; —C(═O)—C(═O)—; —NR^(x)—C(═O)—;     —Z¹—C(═O)—; —Z¹—NR^(x)—C(═O)—; —C(═O)—Z¹—; —NR^(x)—C(═O)—Z¹—;     —S(═O)p-; C(═S)—; —NR^(x)—C(═S)—; —Z¹—C(═S)—; —Z¹—NR^(x)—C(═S)—;     —C(═S)—Z¹—; —NR^(x)—C(═S)—Z¹—; -   Z¹ represents a bivalent radical selected from C₁₋₆alkanediyl,     C₂₋₆alkenediyl or C₂₋₆alkynediyl; wherein each of said     C₁₋₆alkanediyl, C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally be     substituted with hydroxyl or amino; and wherein two hydrogen atoms     attached to the same carbon atom in C₁₋₆alkanediyl may optionally be     replaced by C₁₋₆alkanediyl; -   Y represents NR^(x)—C(═O)—Z²—; —NR^(x)—C(═O)—Z²—NR^(y)—;     —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—; —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—O—;     —NR^(x)—C(═O)—Z²—O—; —NR^(x)—C(═O)—Z²—O—C(═O)—;     —NR^(x)—C(═O)—Z²—C(═O)—; —NR^(x)—C(═O)—Z²—C(═O)—O—;     —NR^(x)—C(═O)—O—Z²—C(═O)—; —NR^(x)—C(═O)—O—Z²—C(═O)—O—;     —NR^(x)—C(═O)—O—Z²—O—C(═O)—; —NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—;     —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—; —C(═O)—Z²—; —C(═O)—Z²—O—;     —C(═O)—NR^(x)—Z²—; —C(═O)—NR^(x)—Z²—O—; —C(═O)—NR^(x)—Z²—C(═O)—O—;     —C(═O)—NR^(x)—Z²—O—C(═O)—; —C(═O)—NR^(x)—O—Z²—;     —C(═O)—NR^(x)—Z²—NR^(y)—; —C(═O)—NR^(x)—Z²—NR^(y)—C(═O)—;     —C(═O)—NR^(x)—Z²—NR^(y)—C(═O)—O—; -   Z² represents a bivalent radical selected from C₁₋₆alkanediyl,     C₂₋₆alkenediyl or C₂₋₆alkynediyl; wherein each of said     C₁₋₆alkanediyl, C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally be     substituted with C₁₋₄alkyloxy, C₁₋₄alkylthio, hydroxyl, cyano or     aryl; and wherein two hydrogen atoms attached to the same carbon     atom in the definition of Z² may optionally be replaced by     C₁₋₆alkanediyl; -   R^(x) represents hydrogen or C₁₋₄alkyl; -   R^(y) represents hydrogen; C₁₋₄alkyl optionally substituted with     C₃₋₆cycloalkyl or aryl or Het; C₂₋₄ alkenyl; or —S(═O)_(p)-aryl; -   R¹ represents C₁₋₁₂alkyl optionally substituted with cyano,     C₁₋₄alkyloxy, C₁₋₄alkyl-oxyC₁₋₄alkyloxy, C₃₋₆cycloalkyl or aryl;     C₂₋₆alkenyl; C₂₋₆alkynyl; C₃₋₆cycloalkyl; adamantanyl; aryl¹;     aryl¹C₁₋₆alkyl; Het¹; or Het¹C₁₋₆alkyl; provided that when Y     represents —NR^(x)—C(═O)—Z²—; —NR^(x)—C(═O)—Z²—NR^(y);     —NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—; —C(═O)—Z²—;     —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—; —C(═O)—NR^(x)—Z²—;     —C(═O)—NR^(x)—O—Z²—; or —C(═O)—NR^(x)—Z²—NR^(y)—; then R¹ may also     represent hydrogen; -   R² represents hydrogen, C₁₋₁₂alkyl, C₂₋₆alkenyl or R³; -   R³ represents C₃₋₆cycloalkyl, phenyl, naphtalenyl,     2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl,     2,3-dihydrobenzofuranyl or a 6-membered aromatic heterocycle     containing 1 or 2 N atoms, wherein said C₃₋₆cycloalkyl, phenyl,     naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl or     6-membered aromatic heterocycle containing 1 or 2 N atoms may     optionally be substituted with at least one substituent, in     particular one, two, three, four or five substituents, each     substituent independently selected from hydroxyl; carboxyl; halo;     C₁₋₆alkyl optionally substituted with hydroxy; polyhaloC₁₋₆alkyl;     C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy;     C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl wherein     C₁₋₆alkyl may optionally be substituted with aryl; cyano;     C₁₋₆alkylcarbonyl; nitro; amino; mono-or di(C₁₋₄alkyl)amino;     C₁₋₄alkylcarbonylamino; —S(═O)_(p)—C₁₋₄alkyl; R⁵R⁴N—C(═O)—;     R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl;     C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy; arylC₁₋₄alkyl;     aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl;     Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—; -   R⁴ represents hydrogen; C₁₋₄alkyl optionally substituted with     hydroxyl or C₁₋₄alkyloxy; R⁷R⁶N—C₁₋₄alkyl; C₁₋₄alkyloxy; Het;     Het-C₁₋₄alkyl; aryl; R⁷R⁶N—C(═O)—C₁₋₄alkyl; -   R⁵ represents hydrogen or C₁₋₄alkyl; -   R⁶ represents hydrogen; C₁₋₄alkyl; C₁₋₄alkylcarbonyl; -   R⁷ represents hydrogen or C₁₋₄alkyl; or -   R⁶ and R⁷ may be taken together with the nitrogen to which they are     attached to form a saturated monocyclic 5, 6 or 7-membered     heterocycle which may further contain one or more heteroatoms each     independently selected from O, S, S(═O)_(p) or N; and which     heterocycle may optionally be substituted with C₁₋₄alkyl; -   R⁸ represents hydrogen, halo, C₁₋₄alkyl, C₁₋₄alkyl substituted with     hydroxyl; -   aryl represents phenyl or phenyl substituted with at least one     substituent, in particular one, two, three, four or five     substituents, each substituent independently being selected from     hydroxyl; carboxyl; halo; C₁₋₆alkyl optionally substituted with     C₁₋₄alkyloxy, amino or mono-or di(C₁₋₄alkyl)amino;     polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with     C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;     C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl; mono-or     di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-or     di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; -   aryl¹ represents phenyl, naphthalenyl or fluorenyl; each of said     phenyl, naphthalenyl or fluorenyl optionally substituted with at     least one substituent, in particular one, two, three, four or five     substituents, each substituent independently being selected from     hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl optionally substituted with     carboxyl, C₁₋₄alkyloxycarbonyl or aryl-C(═O)—; hydroxyC₁₋₆alkyl     optionally substituted with aryl or aryl-C(═O)—; polyhaloC₁₋₆alkyl;     C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy;     C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonyl wherein     C₁₋₆alkyl may optionally be substituted with aryl; cyano;     aminocarbonyl; mono-or di(C₁₋₄alkyl)aminocarbonyl;     C₁₋₆alkylcarbonyl; nitro; amino; mono-or di(C₁₋₆alkyl)amino;     R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—; Het-NR^(x)—;     C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;     HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl;     C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;     arylC₁₋₄alkyl; aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl;     Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—; -   Het represents a monocyclic non-aromatic or aromatic heterocycle     containing at least one heteroatom each independently selected from     O, S, S(═O)_(p) or N; or a bicyclic or tricyclic non-aromatic or     aromatic heterocycle containing at least one heteroatom each     independently selected from O, S, S(═O)_(p) or N; said monocyclic     heterocycle or said bi-or tricyclic heterocycle optionally being     substituted with at least one substituent, in particular one, two,     three, four or five substituents, each substituent independently     being selected from hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl     optionally substituted with C₁₋₄alkyloxy, amino or mono-or     di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally     substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;     C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl; mono-or     di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-or     di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; -   Het¹ represents a monocyclic non-aromatic or aromatic heterocycle     containing at least one heteroatom each independently selected from     O, S, S(═O)_(p) or N; or a bicyclic or tricyclic non-aromatic or     aromatic heterocycle containing at least one heteroatom each     independently selected from O, S, S(═O)_(p) or N; said monocyclic     heterocycle or said bi-or tricyclic heterocycle optionally being     substituted with at least one substituent, in particular one, two,     three, four or five substituents, each substituent independently     being selected from hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl     optionally substituted with carboxyl, C₁₋₄alkyloxycarbonyl or     aryl-C(═O)—; hydroxyC₁₋₆alkyl optionally substituted with aryl or     aryl-C(═O)—; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted     with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;     C₁₋₆alkyloxy-carbonyl wherein C₁₋₆alkyl may optionally be     substituted with aryl; cyano; aminocarbonyl; mono-or     di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-or     di(C₁₋₆alkyl)amino; R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl-NR^(x)—;     aryl-NR^(x)—; Het-NR^(x)—; C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—;     arylC₁₋₄alkyl-NR^(x)—; HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl;     C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—;     aryl; aryloxy; arylC₁₋₄alkyl; aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—;     Het; HetC₁₋₄alkyl; Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—; -   p represents 1 or 2; -   provided that if X represents —O—C(═O)—, then R² represents R³; -   a N-oxide thereof, a pharmaceutically acceptable salt thereof or a     solvate thereof.

Hereinafter, the compounds of formula (I) as defined under a) are indicated as class A compounds, the compounds as defined under b) are indicated as class B compounds, the compounds as defined under c) are indicated as class C compounds, and the compounds as defined under d) are indicated as class D compounds.

In an embodiment, the present invention relates to combinations of a DGAT inhibitor wherein the DGAT inhibitor is selected from

-   a) a compound of class A, class B, class C, or class D; -   and -   b) a PPAR-α agonist or a prodrug thereof.

In an embodiment, the present invention relates to combinations of a DGAT inhibitor wherein the DGAT inhibitor is selected from

-   a) a compound of class A, class B, class C, or class D; -   and -   b) a fibrate.

In an embodiment, the present invention relates to combinations of a DGAT inhibitor wherein the DGAT inhibitor is selected from

-   a) a compound of class A, class B, class C, or class D; -   and -   b) fenofibrate.

In an embodiment, the present invention relates to any of the preceding embodiments wherein the DGAT inhibitor is selected from a compound of Class A.

In an embodiment, the present invention relates to any of the preceding embodiments wherein the DGAT inhibitor is selected from a compound of Class B.

In an embodiment, the present invention relates to any of the preceding embodiments wherein the DGAT inhibitor is selected from a compound of Class C.

In an embodiment, the present invention relates to any of the preceding embodiments wherein the DGAT inhibitor is selected from a compound of Class D.

In an embodiment, the present invention relates to any of the preceding or the following embodiments wherein the PPAR agonist or a prodrug thereof, is a PPAR-α agonist or a prodrug thereof, more in particular a fibrate, even more in particular a fenofibrate.

In an embodiment, the present invention relates to any of the preceding or following embodiments wherein the DGAT inhibitor is a DGAT1 inhibitor.

The present invention also concerns methods for the preparation of compounds of class A, class B, class C or class D, and combinations or pharmaceutical compositions comprising them.

The combinations according to the present invention are suitable for use as a medicament.

The combinations according to the present invention are suitable for reducing food intake, for reducing weight, for suppressing appetite, for inducing satiety; or for the treatment or prevention, in particular treatment, of metabolic disorders, such as obesity and/or obesity related disorders (including, but not limited to, peripheral vascular disease, cardiac failure, myocardial ischaemia, cerebral ischaemia, cardiac myopathies), diabetes, in particular type II diabetes mellitus, and/or complications arising therefrom (such as retinopathy, neuropathy, nephropathy), syndrome X, insulin resistance, impaired glucose tolerance, conditions of impaired fasting glucose, hypoglycemia, hyperglycemia, hyperuricemia, hyperinsulinemia, pancreatitis, hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed dyslipidemia, hypertriglyceridemia, nonalcoholic fatty liver disease, fatty liver, increased mesenteric fat, non-alcoholic steatohepatitis, liver fibrosis, metabolic acidosis, ketosis, dysmetabolic syndrome; dermatological conditions such as acne, psoriasis; cardiovascular diseases, such as atherosclerosis, arteriosclerosis, acute heart failure, congestive heart failure, coronary artery disease, cardiomyopathy, myocardial infarction, angina pectoris, hypertension, hypotension, stroke, ischemia, ischemic reperfusion injury, aneurysm, restenosis or vascular stenosis; alzheimer's disease; neoplastic diseases, such as solid tumors, skin cancer, melanoma, lymphoma or endothelial cancers, e.g., breast cancer, lung cancer, colorectal cancer, stomach cancer, other cancers of the gastrointestinal tract (e.g., esophageal cancer or pancreatic cancer), prostate cancer, kidney cancer, liver cancer, bladder cancer, cervical cancer, uterine cancer, testicular cancer or ovarian cancer.

The combinations according to the present invention are particularly suitable for the treatment of prevention, in particular treatment, of obesity, type II diabetes mellitus; for suppressing appetite, for inducing satiety and/or for reducing food intake.

The present invention also relates to the use of the combinations according to the present invention for the manufacture of a medicament for the treatment or prevention, in particular treatment, of the above mentioned diseases or conditions.

The present invention also relates to the use of a combination of a DGAT inhibitor, in particular a DGAT1 inhibitor, and a PPAR agonist or a prodrug thereof, in particular a PPAR-α agonist or a prodrug thereof, more in particular a fibrate, even more in particular fenofibrate, for the manufacture of a medicament for the prevention or the treatment, in particular for the treatment, of a disease which can benefit from elevated levels of one or more satiety hormones, in particular GLP-1.

The present invention also relates to a product containing a) a DGAT inhibitor, in particular a DGAT1 inhibitor, more in particular a compound of Class A, Class B, Class C or Class D, and (b) an agonist of peroxisome proliferators-activator receptor such as for example fenofibrate, as a combined preparation for simultaneous, separate or sequential use in the treatment of a disease which can benefit from an elevated level of GLP-1 or DGAT inhibition, such as for example diabetes, in particular type II diabetes mellitus, obesity, for suppressing appetite, inducing satiety or for reducing food intake.

In an embodiment, the present invention also relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier, and as active ingredient a therapeutically effective amount of the combinations mentioned hereinbefore or hereinafter.

The present invention further relates to novel compounds, wherein the compound is selected from:

-   N-[4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]phenyl]-4-methoxy-benzeneacetamide     (compound 355 Class D); -   4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide     (compound 151 Class C); -   4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide     (compound 354 Class D); -   4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide     (compound 356 Class D); -   4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide     (compound 152 Class C); -   4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide     (compound 358 Class D); -   4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide     (compound 353 Class D); -   4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide     (compound 357 Class D); -   4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide     (compound 147 Class C); -   4-[4-[[2,6-dichloro-4-[(4-ethyl-1-piperazinyl)methyl]phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide     (compound 360 Class D); -   4-[4-[[2,6-dichloro-4-[(4-ethyl-1-piperazinyl)methyl]phenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide     (compound 359 Class D); -   4-[4-[[2,6-dichloro-4-[[4-(methylsulfonyl)-1-piperazinyl]methyl]phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide     (compound 364 Class D); -   4-[4-[[4-[(4-acetyl-1-piperazinyl)methyl]-2,6-dichlorophenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide     (compound 361 Class D); -   4-[4-[[2,6-dichloro-4-[[4-(methylsulfonyl)-1-piperazinyl]methyl]phenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide     (compound 363 Class D); -   4-[4-[[4-[(4-acetyl-1-piperazinyl)methyl]-2,6-dichlorophenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide     (compound 362 Class D); -   4-[4-[[2,6-dichloro-4-[[4-(methylsulfonyl)-1-piperazinyl]methyl]phenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide     (compound 150 Class C); -   4-[4-[[4-[(4-acetyl-1-piperazinyl)methyl]-2,6-dichlorophenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide     (compound 149 Class C); -   4-[4-[[2,6-dichloro-4-[(4-ethyl-1-piperazinyl)methyl]phenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide     (compound 148 Class C); -   including any stereochemically isomeric forms thereof; -   N-oxides thereof, pharmaceutically acceptable salts thereof or     solvates thereof.

Hereinafter, the novel compounds as defined in the list hereinabove (compounds 147 till 152 from Class C, and compounds 353 till 364 from Class D; including any stereochemically isomeric forms thereof; N-oxides thereof, pharmaceutically acceptable salts thereof or solvates thereof), are indicated as compounds of group Q.

The present invention further relates to the novel compound 4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide (compound 358 Class D); including any stereochemically isomeric forms thereof; N-oxides thereof, pharmaceutically acceptable salts thereof or solvates thereof.

The present invention also relates to a compound of group Q for use as a medicament.

The present invention also relates to a compound of group Q for the prevention or the treatment of a disease mediated by DGAT, in particular the present invention relates to a compound of group Q for the prevention or the treatment of a disease which can benefit from inhibition of DGAT, in particular for the treatment of a disease which can benefit from inhibition of DGAT, in particular DGAT1.

The present invention also relates to a compound of group Q for the prevention or the treatment, in particular for the treatment, of a disease which can benefit from elevated levels of one or more satiety hormones, in particular GLP-1.

The present invention also relates to the use of a compound of group Q for the manufacture of a medicament for the treatment or prevention, in particular treatment, of the above mentioned diseases or conditions.

In an embodiment, the present invention also relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier, and as active ingredient a therapeutically effective amount of a compound of group Q.

The present invention will now be further described. In the following passages, different aspects of the invention are defined in more detail.

DETAILED DESCRIPTION

All terms used are to be construed in accordance with the following definitions, unless the context indicates otherwise. In general, the terms are valid for the compounds of class A, class B, class C and class D, unless it is indicated that a certain definition for a term is only valid for a certain class or subset of classes.

As used hereinbefore or hereinafter C₀₋₃alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 0 (then it represents a direct bond) to 3 carbon atoms such as methyl, ethyl, propyl, 1-methylethyl; C₁₋₂alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having 1 or 2 carbon atoms such as methyl, ethyl; C₁₋₄alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as methyl, ethyl, propyl, 1-methylethyl, butyl; C₁₋₅alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 5 carbon atoms such as the group defined for C₁₋₄alkyl and pentyl, 2-methylbutyl and the like; C₁₋₆alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as the group defined for C₁₋₄alkyl and for C₁₋₅alkyl and hexyl, 2-methylpentyl and the like; C₁₋₁₂alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 12 carbon atoms such as the group defined for C₁₋₆alkyl and heptyl, 2-methylheptyl and the like; C₁₋₆alkanediyl defines straight or branched chain saturated bivalent hydrocarbon radicals having from 1 to 6 carbon atoms such as methylene, 1,2-ethanediyl or 1,2-ethylidene, 1,3-propanediyl or 1,3-propylidene, 1,4-butanediyl or 1,4-butylidene, 1,5-pentanediyl and the like; C₂₋₄alkenyl as a group or part of a group defines straight or branched chain hydrocarbon radicals having from 2 to 4 carbon atoms and having a double bond such as ethenyl, propenyl, butenyl and the like; C₂₋₆alkenyl as a group or part of a group defines straight or branched chain hydrocarbon radicals having from 2 to 6 carbon atoms and having a double bond such as the group defined for C₂₋₄alkenyl and pentenyl, hexenyl, 3-methylbutenyl and the like; C₂₋₆alkenediyl defines straight or branched chain bivalent hydrocarbon radicals having from 2 to 6 carbon atoms and having a double bond such as 1,2-ethenediyl, 1,3-propenediyl, 1,4-butenediyl, 1,5-pentenediyl and the like; C₂₋₆alkynyl defines straight and branched chain hydrocarbon radicals having from 2 to 6 carbon atoms and having a triple bond such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like; C₂₋₆alkynediyl as a group or part of a group defines straight or branched chain bivalent hydrocarbon radicals having from 2 to 6 carbon atoms and having a triple bond such as 1,2-ethynediyl, 1,3-propynediyl, 1,4-butynediyl, 1,5-pentynediyl and the like; C₃₋₆cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term halo is generic to fluoro, chloro, bromo and iodo. As used hereinbefore or hereinafter, polyhaloC₁₋₆alkyl as a group or part of a group is defined as C₁₋₆alkyl substituted with one or more, such as for example 2, 3, 4 or 5 halo atoms, for example methyl substituted with one or more fluoro atoms, for example, difluoromethyl or trifluoromethyl, 1,1-difluoro-ethyl, 1,1-difluoro-2,2,2-trifluoro-ethyl and the like. In case more than one halogen atoms are attached to a C₁₋₆alkyl group within the definition of polyhaloC₁₋₆alkyl, they may be the same or different.

As used herein before, the term (═O) forms a carbonyl moiety when attached to a carbon atom, a sulfoxide moiety when attached to a sulfur atom and a sulfonyl moiety when two of said terms are attached to a sulfur atom. Oxo means ═O.

The radical R¹, as defined hereinabove for the compounds of class B, may be an optionally substituted 5-membered monocyclic heterocycle containing at least 2 heteroatoms, an optionally substituted 6-membered aromatic monocyclic heterocycle or an optionally substituted 5-membered heterocycle containing at least 2 heteroatoms fused with a phenyl, cyclohexyl or a 5-or 6-membered heterocycle.

A 5-membered monocyclic heterocycle as defined hereinabove or hereinafter may be a 5-membered monocyclic non-aromatic (fully saturated or partially saturated) or aromatic heterocycle containing at least 2 heteroatom, in particular 2 or 3 heteroatoms, each independently selected from O, S, S(═O)_(p) or N. Examples of such unsubstituted monocyclic 5-membered heterocycles comprise, but are not limited to, non-aromatic (fully saturated or partially saturated) or aromatic 5-membered monocyclic heterocycles such as for example 1,3-dioxolanyl, imidazolidinyl, thiazolidinyl, dihydrooxazolyl, isothiazolidinyl, isoxazolidinyl, oxadiazolidinyl, triazolidinyl, thiadiazolidinyl, pyrazolidinyl, imidazolinyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl and the like. Optional substituents of the above heterocycles are hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl optionally substituted with carboxyl, C₁₋₄alkyloxy-carbonyl or aryl-C(═O)—; hydroxyC₁₋₆alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonyl wherein C₁₋₆alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono-or di(C₁₋₄alkyl)-aminocarbonyl; C₁₋₆alkylcarbonyl; amino; mono-or di(C₁₋₆alkyl)amino; R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—; Het-NR^(x)—; C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—; HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy; arylC₁₋₄alkyl; aryl-C(═O)—; aryl-C(═O)—C₁₋₄alkyl; Het; HetC₁₋₄alkyl; Het-C(═O)—; Het-C(═O)—C₁₋₄alkyl; Het-O—.

A 6-membered aromatic monocyclic heterocycle as defined hereinabove or hereinafter contains at least one heteroatom, in particular 1, 2 or 3 heteroatoms, each independently selected from O, S, S(═O)_(p) or N. Examples of such unsubstituted monocyclic 6-membered aromatic heterocycles comprise, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl and the like. Optional substituents of the above heterocycles are hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl optionally substituted with carboxyl, C₁₋₄alkyloxycarbonyl or aryl-C(═O)—; hydroxyC₁₋₆alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonyl wherein C₁₋₆alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono-or di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; amino; mono-or di(C₁₋₆alkyl)amino; R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—; Het-NR^(x)—; C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—; HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy; arylC₁₋₄alkyl; aryl-C(═O)—; aryl-C(═O)—C₁₋₄alkyl; Het; HetC₁₋₄alkyl; Het-C(═O)—; Het-C(═O)—C₁₋₄alkyl; Het-O—.

A 5-membered heterocycle containing at least 2 heteroatoms fused with phenyl, cyclohexyl or a 5-or 6-membered heterocycle as defined hereinabove or hereinafter may be a non-aromatic (fully saturated or partially saturated) or aromatic 5-membered heterocycle containing at least 2 heteroatoms, in particular 2 or 3 heteroatoms, each independently selected from O, S, S(═O)_(p) or N, in particular O, S or N, more in particular O or N, fused with phenyl, cyclohexyl or a 5-or 6-membered non-aromatic (fully saturated or partially saturated) or aromatic heterocycle containing at least one heteroatom, in particular 1, 2 or 3 heteroatoms, each independently selected from O, S, S(═O)_(p) or N. Examples of such unsubstituted bicyclic heterocycles comprise, but are not limited to, non-aromatic (fully saturated or partially saturated) or aromatic 8-or 9-membered bicyclic heterocycles such as for example 1,3-benzodioxolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, benzopyrazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, pyrrolopyridyl, thienopyridyl, furopyridyl, isothiazolopyridyl, thiazolopyridyl, isoxazolopyridyl, oxazolopyridyl, pyrazolopyridyl, imidazopyridyl, pyrrolopyrazinyl, thienopyrazinyl, furopyrazinyl, isothiazolopyrazinyl, thiazolopyrazinyl, isoxazolopyrazinyl, oxazolopyrazinyl, pyrazolopyrazinyl, imidazopyrazinyl, pyrrolopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, isothiazolopyrimidinyl, thiazolopyrimidinyl, isoxazolopyrimidinyl, oxazolopyrimidinyl, pyrazolopyrimidinyl, imidazopyrimidinyl, pyrrolopyridazinyl, thienopyridazinyl, furopyridazinyl, isothiazolopyridazinyl, thiazolopyridazinyl, isoxazolopyridazinyl, oxazolopyridazinyl, pyrazolopyridazinyl, imidazopyridazinyl, oxadiazolopyridyl, thiadiazolopyridyl, triazolopyridyl, oxadiazolopyrazinyl, thiadiazolopyrazinyl, triazolopyrazinyl, oxadiazolopyrimidinyl, thiadiazolopyrimidinyl, triazolopyrimidinyl, oxadiazolopyridazinyl, thiadiazolopyridazinyl, triazolopyridazinyl, imidazooxazolyl, imidazothiazolyl, imidazoimidazolyl, imidazopyrazolyl, isoxazolotriazinyl, isothiazolotriazinyl, pyrazolotriazinyl, oxazolotriazinyl, thiazolotriazinyl, imidazotriazinyl, oxadiazolotriazinyl, thiadiazolotriazinyl, triazolotriazinyl and the like. Optional substituents of the above heterocycles are hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl optionally substituted with carboxyl, C₁₋₄alkyloxycarbonyl or aryl-C(═O)—; hydroxyC₁₋₆alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonyl wherein C₁₋₆alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono-or di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; amino; mono-or di(C₁₋₆alkyl)amino; R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—; Het-NR^(x)—; C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—; HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy; arylC₁₋₄alkyl; aryl-C(═O)—; aryl-C(═O)—C₁₋₄alkyl; Het; HetC₁₋₄alkyl; Het-C(═O)—; Het-C(═O)—C₁₋₄alkyl; Het-O—.

The radical Het or Het¹ as defined hereinabove may be an optionally substituted monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom, in particular 1, 2 or 3 heteroatoms, each independently selected from O, S, S(═O)_(p) or N; or an optionally substituted bi-or tricyclic non-aromatic or aromatic heterocycle containing at least one heteroatom, in particular 1, 2, 3, 4 or 5 heteroatoms, each independently selected from O, S, S(═O)_(p) or N. Examples of such unsubstituted monocyclic heterocycles comprise, but are not limited to, non-aromatic (fully saturated or partially saturated) or aromatic 4-, 5-, 6-or 7-membered monocyclic heterocycles such as for example azetidinyl, tetrahydrofuranyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, thiazolidinyl, tetrahydrothienyl, dihydrooxazolyl, isothiazolidinyl, isoxazolidinyl, oxadiazolidinyl, triazolidinyl, thiadiazolidinyl, pyrazolidinyl, piperidinyl, hexahydropyrimidinyl, hexahydropyrazinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, hexahydrodiazepinyl, pyrrolinyl, imidazolinyl, pyrazolinyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl and the like. Examples of such unsubstituted bicyclic or tricyclic heterocycles comprise, but are not limited to, non-aromatic (fully saturated or partially saturated) or aromatic 8- to 17-membered bicyclic or tricyclic heterocycles such as for example decahydroquinolinyl, octahydroindolyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, indolinyl, benzofuryl, isobenzofuryl, benzothienyl, isobenzothienyl, indolizinyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, benzopyrazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinolizinyl, phthalazinyl, quinoxalinyl, quinazolinyl, naphthiridinyl, pteridinyl, benzopyranyl, pyrrolopyridyl, thienopyridyl, furopyridyl, isothiazolopyridyl, thiazolopyridyl, isoxazolopyridyl, oxazolopyridyl, pyrazolopyridyl, imidazopyridyl, pyrrolopyrazinyl, thienopyrazinyl, furopyrazinyl, isothiazolopyrazinyl, thiazolopyrazinyl, isoxazolopyrazinyl, oxazolopyrazinyl, pyrazolopyrazinyl, imidazopyrazinyl, pyrrolopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, isothiazolopyrimidinyl, thiazolopyrimidinyl, isoxazolopyrimidinyl, oxazolopyrimidinyl, pyrazolopyrimidinyl, imidazopyrimidinyl, pyrrolopyridazinyl, thienopyridazinyl, furopyridazinyl, isothiazolopyridazinyl, thiazolopyridazinyl, isoxazolopyridazinyl, oxazolopyridazinyl, pyrazolopyridazinyl, imidazopyridazinyl, oxadiazolopyridyl, thiadiazolopyridyl, triazolopyridyl, oxadiazolopyrazinyl, thiadiazolopyrazinyl, triazolopyrazinyl, oxadiazolopyrimidinyl, thiadiazolopyrimidinyl, triazolopyrimidinyl, oxadiazolopyridazinyl, thiadiazolopyridazinyl, triazolopyridazinyl, imidazooxazolyl, imidazothiazolyl, imidazoimidazolyl, imidazopyrazolyl; isoxazolotriazinyl, isothiazolotriazinyl, pyrazolotriazinyl, oxazolotriazinyl, thiazolotriazinyl, imidazotriazinyl, oxadiazolotriazinyl, thiadiazolotriazinyl, triazolotriazinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and the like. Optional substituents for Het heterocycles are hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl optionally substituted with C₁₋₄alkyloxy, amino or mono-or di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyl-oxycarbonyl; cyano; aminocarbonyl; mono-or di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl. Optional substituents for Het¹ substituents are hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl optionally substituted with carboxyl, C₁₋₄alkyloxycarbonyl or aryl-C(═O)—; hydroxyC₁₋₆alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonyl wherein C₁₋₆alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono-or di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; amino; mono-or di(C₁₋₆alkyl)amino; R⁶R⁵N—C₁₋₆alkyl; C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—; Het-NR^(x)—; C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—; HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy; arylC₁₋₄alkyl; aryl-C(═O)—; aryl-C(═O)—C₁₋₄alkyl; Het; HetC₁₋₄alkyl; Het-C(═O)—; Het-C(═O)—C₁₋₄alkyl; Het-O—.

Examples of a 6-membered aromatic heterocycle containing 1 or 2 N atoms in the definition of R³ (class B and class D) and R² (class C) are pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl.

When any variable occurs more than one time in any constituent (e.g. aryl, Het), each definition is independent.

The term Het or Het¹ is meant to include all the possible isomeric forms of the heterocycles, for instance, pyrrolyl comprises 1H-pyrrolyl and 2H-pyrrolyl.

The term R¹ (in class B) is meant to include all the possible isomeric forms of the heterocycles, for instance, pyrrolyl comprises 1H-pyrrolyl and 2H-pyrrolyl.

The carbocycles or heterocycles covered by the terms aryl, Het, aryl¹, Het¹, R¹ (in class B) or R³ (in class B, class C or class D) may be attached to the remainder of the molecule of formula (I) of class A, class B, class C or class D through any ring carbon or heteroatom as appropriate, if not otherwise specified. Thus, for example, when the heterocycle is imidazolyl, it may be 1-imidazolyl, 2-imidazolyl, 4-imidazolyl and the like, or when the carbocycle is naphthalenyl, it may be 1-naphthalenyl, 2-naphthalenyl and the like.

Lines drawn from substituents into ring systems indicate that the bond may be attached to any of the suitable ring atoms.

When X is defined as for instance —NR^(x)—C(═O)—, this means that the nitrogen of NR^(x) is linked to the R² substituent (not applicable for class A) and the carbon atom of C(═O) is linked to the nitrogen of the ring

Thus the left part of the bivalent radical in the definition of X is linked to the R² substituent and the right part of the bivalent radical in the definition of X is linked to the ring moiety

When Y is defined for instance as —NR^(x)—C(═O)— in class A or class C, this means that the nitrogen of NR^(x) is linked to the phenyl moiety and the carbon atom of C(═O) is linked to the R¹ substituent. Thus the left part of the bivalent radical in the definition of Y is linked to the phenyl moiety and the right part of the bivalent radical in the definition of Y is linked to the R¹ substituent.

When Y is defined as for instance —NR^(x)—C(═O)—Z²— in class D, this means that the nitrogen of NR^(x) is linked to the phenyl ring and the Z² is linked to the R¹ substituent. Thus the left part of the bivalent radical in the definition of Y is linked to the phenyl ring and the right part of the bivalent radical in the definition of Y is linked to R¹ substituent.

Some of the compounds of class A, class B, class C or class D may also exist in their tautomeric form. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.

Whenever used hereinbefore or hereinafter that substituents can be selected each independently out of a list of numerous definitions, such as for example for R² and R³ in class A, R⁴ and R⁵ in class B and class D, and R³ and R⁴ in class C, all possible combinations are intended which are chemically possible.

For therapeutic use, salts of the compounds of class A, class B, class C or class D are those wherein the counterion is pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.

The pharmaceutically acceptable salts as mentioned hereinbefore or hereinafter are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of class A, class B, class C or class D are able to form. The latter can conveniently be obtained by treating the base form with such appropriate acids as inorganic acids, for example, hydrohalic acids, e.g. hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfonic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely the salt form can be converted by treatment with alkali into the free base form.

The compounds of class A, class B, class C or class D containing acidic protons may be converted into their therapeutically active non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. The pharmaceutically acceptable salts as mentioned hereinbefore or hereinafter are meant to also comprise the therapeutically active non-toxic metal or amine addition salt forms (base addition salt forms) which the compounds of class A, class B, class C or class D are able to form. Appropriate base addition salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline, the benzathine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.

Conversely the salt form can be converted by treatment with acid into the free acid form.

The term salt also comprises the quaternary ammonium salts (quaternary amines) which the compounds of class A, class B, class C or class D are able to form by reaction between a basic nitrogen of a compound of class A, class B, class C or class D and an appropriate quaternizing agent, such as, for example, an optionally substituted C₁₋₆alkylhalide, arylhalide, C₁₋₆alkyl-carbonylhalide, arylcarbonylhalide, or arylC₁₋₆alkylhalide, e.g. methyliodide or benzyliodide. Other reactants with good leaving groups may also be used, such as for example C₁₋₆alkyl trifluoromethanesulfonates, C₁₋₆alkyl methanesulfonates, and C₁₋₆alkyl p-toluenesulfonates. A quaternary amine has a positively charged nitrogen. Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate, acetate, triflate, sulfate, sulfonate. The counterion of choice can be introduced using ion exchange resins.

The term solvate comprises the hydrates and solvent addition forms which the compounds of class A, class B, class C or class D are able to form, as well as salts thereof. Examples of such forms are e.g. hydrates, alcoholates and the like.

The N-oxide forms of the present compounds are meant to comprise the compounds of class A, class B, class C or class D wherein one or several tertiary nitrogen atoms are oxidized to the so-called N-oxide.

It will be appreciated that some of the compounds of class A, class B, class C or class D may contain one or more centers of chirality and exist as stereochemically isomeric forms.

The term “stereochemically isomeric forms” as used hereinbefore or hereinafter defines all the possible stereoisomeric forms which the compounds of class A, class B, class C or class D may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure as well as each of the individual isomeric forms of the basis molecular structure and their N-oxides, salts or solvates, substantially free, i.e. associated with less than 10%, preferably less than 5%, in particular less than 2% and most preferably less than 1% of the other isomers. Thus, when a compound of class A, class B, class C or class D is for instance specified as (E), this means that the compound is substantially free of the (Z) isomer.

In particular, stereogenic centers may have the R-or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have either the cis-or trans-configuration. Compounds encompassing double bonds can have an E (entgegen) or Z (zusammen)-stereochemistry at said double bond. The terms cis, trans, R, S, E and Z are well known to a person skilled in the art.

Stereochemically isomeric forms of the compounds of class A, class B, class C or class D are obviously intended to be embraced within the scope of this invention.

Following CAS-nomenclature conventions, when two stereogenic centers of known absolute configuration are present in a molecule, an R or S descriptor is assigned (based on Cahn-Ingold-Prelog sequence rule) to the lowest-numbered chiral center, the reference center. The configuration of the second stereogenic center is indicated using relative descriptors [R*,R*] or [R*,S*], where the first R* is always specified as the reference center and [R*,R*] indicates centers with the same chirality and [R*,S*] indicates centers of unlike chirality. For example, if the lowest-numbered chiral center in the molecule has an S configuration and the second center is R, the stereo descriptor would be specified as S-[R*,S*]. If “α” and “β” are used: the position of the highest priority substituent on the asymmetric carbon atom in the ring system having the lowest ring number, is arbitrarily always in the “α” position of the mean plane determined by the ring system. The position of the highest priority substituent on the other asymmetric carbon atom in the ring system relative to the position of the highest priority substituent on the reference atom is denominated “α”, if it is on the same side of the mean plane determined by the ring system, or “β”, if it is on the other side of the mean plane determined by the ring system.

The compounds of (I) may be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of class A, class B, class C or class D may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of class A, class B, class C or class D involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.

Whenever used hereinbefore or hereinafter, the term “compounds of class A”, “compounds of class B”, “compounds of class C” or “compounds of class D” or any subgroup thereof, is meant to also include their N-oxide forms, their salts, their stereochemically isomeric forms and their solvates. Of special interest are those compounds of class A, class B, class C or class D which are stereochemically pure.

Whenever used hereinbefore or hereinafter, the term “compounds of group Q”, is meant to also include their N-oxide forms, their salts, their stereochemically isomeric forms and their solvates. Of special interest are those compounds group Q which are stereochemically pure.

By PPAR agonist, in particular PPAR-α agonist, is meant a compound or a prodrug thereof, or a composition containing said compound or prodrug thereof; which directly or indirectly stimulates or increases an in vivo or in vitro reaction typical for the PPAR receptor, in particular the PPAR-α receptor, e.g. transcriptional regulation activity, as measured by an assay known to one skilled in the art such as, for example, described in Kuwabara K, Murakami K, Todo M, Aoki T, Asaki T, Mura M, and Yano J (2004) A novel selective peroxisome proliferator-activated receptor a agonist, 2-methyl-c-5-[4-[5-methyl-2-(4-methylphenyl)-4-oxazolyl]butyl]-1,3-dioxane-r-2-carboxylic acid (NS-220), potently decreases plasma triglyceride and glucose levels and modifies lipoprotein profiles in KK-A^(y) mice. J Pharmacol Exp Ther Vol. 309, No. 3: 970-977.

Non-limiting examples of PPAR-α agonists or prodrugs thereof include natural and synthetic agonists, such as eicosanoids, leukotriene β₄, carbaprostacyclin, nonsteroidal anti-inflammatory drugs, pirinixic acid (WY-14643; PPAR-α/γ agonist), phthalate ester plasticizers, pterostilbene, fibrates or active metabolites thereof, α-substituted phenyl-propanoic acid derivatives, isoxazolyl-serine-based compounds.

A preferred PPAR-α agonist or a prodrug thereof is a fibrate compound including, but not limited to fenofibrate (fenofibric acid as active metabolite), bezafibrate, clofibrate, ciprofibrate, etofibrate, ABT-335 (which is the choline salt of fenofibric acid), pirifibrate, beclofibrate or gemfibrozil (a PPAR-α modulator) and analogues, derivatives and pharmaceutically acceptable salts thereof.

Whenever the term ‘prodrug’ is used within the context of this invention, this refers to a pharmacological substance (drug) that is administered in an inactive or significantly less active form. Once administered, the prodrug is metabolised in vivo into an active metabolite. For example, the prodrug fenofibrate (ester) is metabolised to fenofibric acid which is the active metabolite (PPAR-α agonist).

A preferred fibrate is fenofibrate.

In the present invention, fibrates include fibric acid derivatives and pharmaceutically acceptable salts of such fibric acid derivatives.

The next embodiments of the present invention are those combinations of a DGAT inhibitor, more in particular a DGAT1 inhibitor and a PPAR agonist, in particular a PPAR-α agonist, more in particular a fibrate, even more in particular fenofibrate; wherein the DGAT inhibitor is selected from compounds of Class A. Preferred embodiments of compounds of class A are:

-   A-1) compounds of class A having the following formula (D

-   including any stereochemically isomeric form thereof, wherein -   A represents CH or N; -   X represents O or NR^(x); -   the dotted line represents an optional bond in case A represents a     carbon atom; -   Y represents a direct bond; —NR^(x)—C(═O)—; —C(═O)—NR^(x)—;     —NR^(x)—C(═O)—Z—; —NR^(x)—C(═O)—Z—NR^(y)—;     —NR^(x)—C(═O)—Z—NR^(y)—C(═O)—; —NR^(x)—C(═O)—Z—NR^(y)—C(═O)—O—;     —NR^(x)—C(═O)—Z—O—; —NR^(x)—C(═O)—Z—O—C(═O)—;     —NR^(x)—C(═O)—Z—C(═O)—; —NR^(x)—C(═O)—Z—C(═O)—O—;     —NR^(x)—C(═O)—O—Z—C(═O)—; —NR^(x)—C(═O)—O—Z—C(═O)—O—;     —NR^(x)—C(═O)—O—Z—O—C(═O)—; —NR^(x)—C(═O)—Z—C(═O)—NR^(y)—;     —NR^(x)—C(═O)—Z—NR^(y)—C(═O)—NR^(y)—; —C(═O)—Z—; —C(═O)—Z—O—;     —C(═O)—NR^(x)—Z—; —C(═O)—NR^(x)—Z—O—; —C(═O)—NR^(x)—Z—C(═O)—O—;     —C(═O)—NR^(x)—Z—O—C(═O)—; —C(═O)—NR^(x)—O—Z—;     —C(═O)—NR^(x)—Z—NR^(y)—; —C(═O)—NR^(x)—Z—NR^(y)—C(═O)—;     —C(═O)—NR^(x)—Z—NR^(y)—C(═O)—O—; -   Z represents a bivalent radical selected from C₁₋₆alkanediyl,     C₂₋₆alkenediyl or C₂₋₆alkynediyl; wherein each of said     C₁₋₆alkanediyl, C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally be     substituted with C₁₋₄alkyloxy, C₁₋₄alkylthio, hydroxyl, cyano or     aryl; and wherein two hydrogen atoms attached to the same carbon     atom in the definition of Z may optionally be replaced by     C₁₋₆alkanediyl; -   R^(x) represents hydrogen or C₁₋₄alkyl; -   R^(y) represents hydrogen; C₁₋₄alkyl optionally substituted with     C₃₋₆cycloalkyl or aryl or Het; C₂₋₄ alkenyl; or —S(═O)_(p)-aryl; -   R¹ represents C₁₋₁₂alkyl optionally substituted with cyano,     C₁₋₄alkyloxy, C₁₋₄alkyl-oxyC₁₋₄alkyloxy, C₃₋₆cycloalkyl or aryl;     C₂₋₆alkenyl; C₂₋₆alkynyl; C₃₋₆cycloalkyl; aryl¹; aryl¹C₁₋₆alkyl;     Het¹; or Het¹C₁₋₆alkyl; provided that when Y represents     —NR^(x)—C(═O)—Z—; —NR^(x)—C(═O)—Z—NR^(y);     —NR^(x)—C(═O)—Z—C(═O)—NR^(y)—; —C(═O)—Z—;     —NR^(x)—C(═O)—Z—NR^(y)—C(═O)—NR^(y)—; —C(═O)—NR^(x)—Z—;     —C(═O)—NR^(x)—O—Z—; or —C(═O)—NR^(x)—Z—NR^(y)—; then R¹ may also     represent hydrogen; -   R² and R³ each independently represent hydrogen; hydroxyl; carboxyl;     halo; C₁₋₆alkyl; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally     substituted with C₁₋₄alkyloxy; C₁₋₆ alkylthio; polyhaloC₁₋₆alkyloxy;     C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl; mono-or     di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-or     di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; -   R⁴ represents hydrogen; hydroxyl; carboxyl; halo; C₁₋₆alkyl;     polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with     C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy;     C₁₋₆alkyloxycarbonyl wherein C₁₋₆alkyl may optionally be substituted     with aryl; cyano; C₁₋₆alkylcarbonyl; nitro; amino; mono-or     di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; R⁶R⁵N—C(═O)—;     R⁶R⁵N—C₁₋₆alkyl; C₃₋₆cycloalkyl; aryl; aryloxy; arylC₁₋₄alkyl;     aryl-C(═O)—; Het; HetC₁₋₄alkyl; Het-C(═O)—; Het-O—; -   R⁵ represents hydrogen; C₁₋₄alkyl optionally substituted with     hydroxyl or C₁₋₄alkyloxy; R⁸R⁷N—C₁₋₄alkyl; C₁₋₄alkyloxy; Het; aryl;     R⁸R⁷N—C(═O)—C₁₋₄alkyl; -   R⁶ represents hydrogen or C₁₋₄alkyl; -   R⁷ represents hydrogen; C₁₋₄alkyl; C₁₋₄alkylcarbonyl; -   R⁸ represents hydrogen or C₁₋₄alkyl; or -   R⁷ and R⁸ may be taken together with the nitrogen to which they are     attached to form a saturated monocyclic 5, 6 or 7-membered     heterocycle which may further contain one or more heteroatoms     selected from O, S, S(═O)_(p) or N; and which heterocycle may     optionally be substituted with C₁₋₄alkyl; -   aryl represents phenyl or phenyl substituted with at least one     substituent, in particular one, two, three, four or five     substituents, each substituent independently being selected from     hydroxyl; carboxyl; halo; C₁₋₆alkyl optionally substituted with     C₁₋₄alkyloxy, amino or mono-or di(C₁₋₄alkyl)amino;     polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with     C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;     C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl; mono-or     di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-or     di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; -   aryl¹ represents phenyl, naphthalenyl or fluorenyl; each of said     phenyl, naphthalenyl or fluorenyl optionally substituted with at     least one substituent, in particular one, two, three, four or five     substituents, each substituent independently being selected from     hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl optionally substituted with     aryl-C(═O)—; hydroxyC₁₋₆alkyl optionally substituted with aryl or     aryl-C(═O)—; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted     with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;     C₁₋₆alkyloxy-carbonyl wherein C₁₋₆alkyl may optionally be     substituted with aryl; cyano; aminocarbonyl; mono-or     di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-or     di(C₁₋₆alkyl)amino; C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—;     Het-NR^(x)—; C₃₋₆cycloalkylC₁₋₄alkyl-NR⁸—; arylC₁₋₄alkyl-NR^(x)—;     HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl;     C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;     arylC₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl; Het-C(═O)—; Het-O—; -   Het represents a monocyclic non-aromatic or aromatic heterocycle     containing at least one heteroatom selected from O, S, S(═O)_(p) or     N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle     containing at least one heteroatom selected from O, S, S(═O)_(p) or     N; said monocyclic heterocycle or said bi-or tricyclic heterocycle     optionally being substituted with at least one substituent, in     particular one, two, three, four or five substituents, each     substituent independently being selected from hydroxyl; oxo;     carboxyl; halo; C₁₋₆alkyl optionally substituted with C₁₋₄alkyloxy,     amino or mono-or di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy     optionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio;     polyhaloC₁₋₆alkyloxy; C₁₋₆alkyl-oxycarbonyl; cyano; aminocarbonyl;     mono-or di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino;     mono-or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; -   Het¹ represents a monocyclic non-aromatic or aromatic heterocycle     containing at least one heteroatom selected from O, S, S(═O)_(p) or     N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle     containing at least one heteroatom selected from O, S, S(═O)_(p) or     N; said monocyclic heterocycle or said bi-or tricyclic heterocycle     optionally being substituted with at least one substituent, in     particular one, two, three, four or five substituents, each     substituent independently being selected from hydroxyl; oxo;     carboxyl; halo; C₁₋₆alkyl optionally substituted with aryl-C(═O)—;     hydroxyC₁₋₆alkyl optionally substituted with aryl or aryl-C(═O)—;     polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with     C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;     C₁₋₆alkyloxy-carbonyl wherein C₁₋₆alkyl may optionally be     substituted with aryl; cyano; aminocarbonyl; mono-or     di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-or     di(C₁₋₆alkyl)amino; C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—;     Het-NR^(x)—; C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;     HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl;     C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;     arylC₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl; Het-C(═O)—; Het-O—; -   p represents 1 or 2; -   a N-oxide thereof, a pharmaceutically acceptable salt thereof or a     solvate thereof; -   or -   A-2) compounds of class A or any subgroup thereof as mentioned     hereinbefore as embodiment, wherein X represents NR^(x), in     particular NH; -   or -   A-3) compounds of class A or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment, wherein X     represents O; -   or -   A-4) compounds of class A or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein A represents     N; -   or -   A-5) compounds of class A or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein A represents     CH, in particular wherein A represents CH and the dotted line does     not represent a bond; -   or -   A-6) compounds of class A or any subgroup thereof as mentioned     hereinbefore as embodiment wherein Y represents —NR^(x)—C(═O)—;     —NR^(x)—C(═O)—Z—, —NR^(x)—C(═O)—Z—NR^(y)—; —NR^(x)—C(═O)—Z—O—C(═O)—;     in particular wherein Y represents —NR^(x)—C(═O)— or     —NR^(x)—C(═O)—Z— with Z representing C₁₋₆alkanediyl; -   or -   A-7) compounds of class A or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein Y represents     a direct bond, in particular wherein Y represents a direct bond and     R¹ represents Het¹; -   or -   A-8) compounds of class A or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein Y represents     —NR^(x)—C(═O)—, in particular wherein Y represents —NR^(x)—C(═O)—     and R¹ represents Aryl¹ or Het¹; -   or -   A-9) compounds of class A or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein Y represents     —NR^(x)—C(═O)—Z—NR^(y)—, in particular wherein Y represents     —NR^(x)—C(═O)—Z—NR^(y)— and R¹ represents Aryl¹ or Het¹; -   or -   A-10) compounds of class A or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein Y represents     —NR^(x)—C(═O)—Z—C(═O)—O— or —NR^(x)—C(═O)—Z—O—C(═O)—, in particular     —NR^(x)—C(═O)—Z—O—C(═O)—; -   or -   A-11) compounds of class A or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein R² or R³     each independently represent hydrogen, halo or C₁₋₆alkyl, in     particular both R² and R³ represent halo, more in particular both R²     and R³ represent chloro or fluoro; -   or -   A-12) compounds of class A or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein R⁴ is placed     in para position; -   or -   A-13) compounds of class A or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein R⁴     represents hydrogen; carboxyl; C₁₋₆alkyloxycarbonyl; amino; mono-or     di(C₁₋₄alkyl)amino; R⁶R⁵N—C(═O)—; R⁶R⁵N—C₁₋₆alkyl; Het-C(═O)— or     HetC₁₋₄alkyl, in particular Het-C(═O)— or HetC₁₋₄alkyl; -   or -   A-14) compounds of class A or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein R⁴ is placed     in para position and represents hydrogen; carboxyl;     C₁₋₆alkyloxy-carbonyl; amino; mono-or di(C₁₋₄alkyl)amino;     R⁶R⁵N—C(═O)—; R⁶R⁵N—C₁₋₆alkyl; Het-C(═O)— or HetC₁₋₄alkyl, in     particular Het-C(═O)— or HetC₁₋₄alkyl; -   or -   A-15) compounds of class A or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein p represents     2; -   or -   A-16) compounds of class A or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein R¹     represents hydrogen; C₁₋₁₂alkyl; aryl¹ or Het¹; in particular Aryl¹     or Het¹; more in particular Aryl¹; more in particular optionally     substituted phenyl wherein the optional substituent is preferably     selected from aryl, Het or C₁₋₆alkyloxy; even more in particular     phenyl; -   or -   A-17) compounds of class A or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein Z represents     C₁₋₆alkanediyl; -   or -   A-18) compounds of class A or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein R^(x)     represents hydrogen; -   or -   A-19) compounds of class A or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein R^(y)     represents hydrogen; -   or -   A-20) compounds of class A or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein R⁹     represents hydrogen; -   or -   A-21) compounds of class A or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein R⁹     represents halo, C₁₋₄alkyl, C₁₋₄alkyl substituted with hydroxyl; -   or -   A-22) compounds of class A or any subgroup thereof as mentioned     hereinbefore as embodiment wherein one or more, preferably all, of     the following restrictions apply: -   a) X represents NH; -   b) R² represents hydrogen, halo or C₁₋₆alkyl; in particular halo;     more in particular chloro; -   c) R³ represents hydrogen, halo or C₁₋₆alkyl; in particular halo;     more in particular chloro; -   d) R⁴ represents hydrogen; -   e) A represents N; -   f) the dotted line does not represent an additional bond; -   g) Y represents —NR^(x)—C(═O)—Z—; -   h) Z represents C₁₋₆alkanediyl; -   i) R¹ represents aryl¹; in particular optionally substituted phenyl;     more in particular phenyl. -   j) R^(x) represents hydrogen; -   or -   A-23) compounds of class A or any subgroup thereof as mentioned     hereinbefore as embodiment wherein one or more, preferably all, of     the following restrictions apply: -   a) X represents NH or O; -   b) R² represents hydrogen, halo or C₁₋₆alkyl; in particular halo;     more in particular chloro or fluoro; -   c) R³ represents hydrogen, halo or C₁₋₆alkyl; in particular halo;     more in particular chloro or fluoro; -   d) R⁴ represents hydrogen; carboxyl; C₁₋₆alkyloxycarbonyl;     Het-C(═O)— or HetC₁₋₄alkyl, in particular Het-C(═O)— or     HetC₁₋₄alkyl; -   e) A represents N; -   f) the dotted line does not represent a bond; -   g) Y represents —NR^(x)—C(═O)—; —NR^(x)—C(═O)—Z—,     —NR^(x)—C(═O)—Z—NR^(y)—; —NR^(x)—C(═O)—Z—O—C(═O)—; -   h) Z represents C₁₋₆alkanediyl; -   i) R¹ represents hydrogen; C₁₋₁₂alkyl; aryl¹ or Het¹; in particular     aryl¹; more in particular optionally substituted phenyl wherein the     optional substituent is preferably selected from aryl, Het or     C₁₋₆alkyloxy; more in particular phenyl; -   j) R^(x) represents hydrogen; -   k) R^(y) represents hydrogen; -   l) R⁹ represents hydrogen; -   m) R⁴ is placed in para position; -   or -   A-24) compounds of class A selected from

-   including any stereochemically isomeric form thereof; -   a N-oxide thereof, a pharmaceutically acceptable salt thereof or a     solvate thereof.

The next embodiments of the present invention are those combinations of a DGAT inhibitor, more in particular a DGAT1 inhibitor and a PPAR agonist, in particular a PPAR-α agonist, more in particular a fibrate, even more in particular fenofibrate; wherein the DGAT inhibitor is selected from compounds of Class B. Preferred embodiments of compounds of class B are:

-   B-1) compounds of class B having the following formula (I)

-   including any stereochemically isomeric form thereof, wherein -   A represents CH or N; -   the dotted line represents an optional bond in case A represents a     carbon atom; -   X represents —NR^(x)—C(═O)—; —Z—C(═O)—; —Z—NR^(x)—C(═O)—; —S(═O)p-;     C(═S)—; —NR^(x)—C(═S)—; —Z—C(═S)—; —Z—NR^(x)—C(═S)—; -   Z represents a bivalent radical selected from C₁₋₆alkanediyl,     C₂₋₆alkenediyl or C₂₋₆alkynediyl; wherein each of said     C₁₋₆alkanediyl, C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally be     substituted with hydroxyl; -   R^(x) represents hydrogen or C₁₋₄alkyl; -   R¹ represents a 5-membered monocyclic heterocycle containing at     least 2 heteroatoms; a 6-membered aromatic monocyclic heterocycle;     or a 5-membered heterocycle containing at least 2 heteroatoms fused     with phenyl, cyclohexyl or a 5-or 6-membered heterocycle; wherein     each of said heterocycles may optionally be substituted with at     least one substituent, in particular one, two, three, four or five     substituents, each substituent independently being selected from     hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl optionally substituted with     aryl-C(═O)—; hydroxyC₁₋₆alkyl optionally substituted with aryl or     aryl-C(═O)—; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted     with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;     C₁₋₆alkyloxy-carbonyl wherein C₁₋₆alkyl may optionally be     substituted with aryl; cyano; aminocarbonyl; mono-or     di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-or     di(C₁₋₆alkyl)amino; C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—;     Het-NR^(x)—; C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;     HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl;     C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;     arylC₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl; Het-C(═O)—; Het-O—; -   R² represents R³; -   R³ represents C₃₋₆cycloalkyl, phenyl, naphtalenyl,     2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, wherein said     C₃₋₆cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl,     1,3-benzodioxolyl may optionally be substituted with at least one     substituent, in particular one, two, three, four or five     substituents, each substituent independently selected from hydroxyl;     carboxyl; halo; C₁₋₆alkyl optionally substituted with hydroxy;     polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with     C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy;     C₁₋₆alkyloxy-carbonyl wherein C₁₋₆alkyl may optionally be     substituted with aryl; cyano; C₁₋₆alkylcarbonyl; nitro; amino;     mono-or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; R⁵R⁴N—C(═O)—;     R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl;     C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy; arylC₁₋₄alkyl; aryl-C(═O)—;     Het; HetC₁₋₄alkyl; Het-C(═O)—; Het-O—; -   R⁴ represents hydrogen; C₁₋₄alkyl optionally substituted with     hydroxyl or C₁₋₄alkyloxy; R⁷R⁶N—C₁₋₄alkyl; C₁₋₄alkyloxy; Het; aryl;     R⁷R⁶N—C(═O)—C₁₋₄alkyl; -   R⁵ represents hydrogen or C₁₋₄alkyl; -   R⁶ represents hydrogen; C₁₋₄alkyl; C₁₋₄alkylcarbonyl; -   R⁷ represents hydrogen or C₁₋₄alkyl; or -   R⁶ and R⁷ may be taken together with the nitrogen to which they are     attached to form a saturated monocyclic 5, 6 or 7-membered     heterocycle which may further contain one or more heteroatoms     selected from O, S, S(═O)_(p) or N; and which heterocycle may     optionally be substituted with C₁₋₄alkyl; -   aryl represents phenyl or phenyl substituted with at least one     substituent, in particular one, two, three, four or five     substituents, each substituent independently being selected from     hydroxyl; carboxyl; halo; C₁₋₆alkyl optionally substituted with     C₁₋₄alkyloxy, amino or mono-or di(C₁₋₄alkyl)amino;     polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with     C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;     C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl; mono-or     di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-or     di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; -   Het represents a monocyclic non-aromatic or aromatic heterocycle     containing at least one heteroatom selected from O, S, S(═O)_(p) or     N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle     containing at least one heteroatom selected from O, S, S(═O)_(p) or     N; said monocyclic heterocycle or said bi-or tricyclic heterocycle     optionally being substituted with at least one substituent, in     particular one, two, three, four or five substituents, each     substituent independently being selected from hydroxyl; oxo;     carboxyl; halo; C₁₋₆alkyl optionally substituted with C₁₋₄alkyloxy,     amino or mono-or di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy     optionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio;     polyhaloC₁₋₆alkyloxy; C₁₋₆alkyl-oxycarbonyl; cyano; aminocarbonyl;     mono-or di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino;     mono-or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; -   p represents 1 or 2; -   a N-oxide thereof, a pharmaceutically acceptable salt thereof or a     solvate thereof; -   or -   B-2) compounds of class B or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein X represents     —NR^(x)—C(═O)—; —Z—C(═O)—; —Z—NR^(x)—C(═O)—; —S(═O)p-;     —NR^(x)—C(═S)— or —O—C(═O)—; in particular X represents     —NR^(x)—C(═O)—; —Z—C(═O)—; —Z—NR^(x)—C(═O)—; more in particular X     represents —NR^(x)—C(═O)— or —Z—C(═O)—; -   or -   B-3) compounds of class B or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein A represents     N; -   or -   B-4) compounds of class B or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein A represents     CH, in particular wherein A represents CH and the dotted line does     not represent a bond; -   or -   B-5) compounds of class B or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein R¹     represents a 5-membered monocyclic heterocycle containing at least 2     heteroatoms, in particular pyrazolyl, triazolyl or oxadiazolyl; a     6-membered monocyclic aromatic heterocycle, in particular     pyrimidinyl; or a 5-membered aromatic heterocycle containing at     least 2 heteroatoms fused with a 5-membered heterocycle, in     particular imidazopyrazolyl or imidazothiazolyl; wherein each of     said heterocycles may optionally be substituted, preferably with one     or two substituents. Particular substituents of said heterocycles     include oxo, C₁₋₆alkyl optionally substituted with aryl-C(═O)— or     C₁₋₄alkyloxycarbonyl; hydroxyC₁₋₆alkyl optionally substituted with     aryl or aryl-C(═O)—; amino; mono-or di(C₁₋₆alkyl)amino;     R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—; Het-NR^(x)—;     C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;     HetC₁₋₄alkyl-NR^(x)—; C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl; aryl;     aryloxy; arylC₁₋₄alkyl; aryl-C(═O)—; aryl-C(═O)—C₁₋₄alkyl; Het;     HetC₁₋₄alkyl; Het-C(═O)—; Het-C(═O)—C₁₋₄alkyl; Het-O—; more in     particular C₁₋₆alkyl optionally substituted with aryl-C(═O)— or     C₁₋₄alkyloxycarbonyl; hydroxyC₁₋₆alkyl optionally substituted with     aryl; mono-or di(C₁₋₆alkyl)amino; R⁵R⁴N—C₁₋₆alkyl;     C₃₋₆cycloalkyl-NR^(x)—; Het-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;     C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl; aryl; arylC₁₋₄alkyl;     aryl-C(═O)—C₁₋₄alkyl or Het; -   or -   B-6) compounds of class B or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein the compound     of class B is a compound of formula (I′)

-   wherein R^(3a) and R^(3b) each independently represent hydrogen;     hydroxyl; carboxyl; halo; C₁₋₆alkyl optionally substituted with     hydroxyl; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted     with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;     C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl; mono-or     di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-or     di(C₁₋₄alkyl)amino; C₁₋₄alkylcarbonylamino; —S(═O)_(p)—C₁₋₄alkyl;     and wherein R^(3c) represents hydrogen; hydroxyl; carboxyl; halo;     C₁₋₆alkyl; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted     with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy;     C₁₋₆alkyloxycarbonyl wherein C₁₋₆alkyl may optionally be substituted     with aryl; cyano; C₁₋₆alkylcarbonyl; nitro; amino; mono-or     di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; R⁵R⁴N—C(═O)—;     R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cyclo-alkyl; aryl; aryloxy; arylC₁₋₄alkyl;     aryl-C(═O)—; Het; HetC₁₋₄alkyl; Het-C(═O)—; Het-O—. -   or -   B-7) compounds of class B or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein the compound     of class B is a compound of formula (I″)

-   wherein R^(3a) and R^(3b) each independently represent hydrogen;     hydroxyl; carboxyl; halo; C₁₋₆alkyl; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy     optionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio;     polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl;     mono-or di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino;     mono-or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; and wherein R^(3c)     represents hydrogen; hydroxyl; carboxyl; halo; C₁₋₆alkyl optionally     substituted with hydroxyl; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy     optionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio;     polyhalo-C₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl wherein C₁₋₆alkyl may     optionally be substituted with aryl; cyano; C₁₋₆alkylcarbonyl;     nitro; amino; mono-or di(C₁₋₄alkyl)amino; C₁₋₄alkylcarbonylamino;     —S(═O)_(p)—C₁₋₄alkyl; R⁵R⁴N—C(═O)—; R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl;     aryl; aryloxy; arylC₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl;     Het-C(═O)—; Het-O—; -   or -   B-8) compounds of class B or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein the compound     of formula (I) is a compound of formula (I′) or (I″) and wherein     R^(3a) and R^(3b) each independently represent halo,     polyhaloC₁₋₆alkyl, C₁₋₆alkyl or C₁₋₆alkyloxy, in particular both     R^(3a) and R^(3b) represent halo, more in particular both R^(3a) and     R^(3b) represent chloro; -   or -   B-9) compounds of class B or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein the compound     of class B is a compound of formula (I′) or (I″) and wherein R^(3c)     represents hydrogen, hydroxyl, carboxyl; halo; amino; mono-or     di-(C₁₋₄alkyl)amino; C₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl;     C₁₋₆alkylthio; C₁₋₄alkylcarbonylamino; R⁵R⁴N—C(═O)—;     R⁵R⁴N—C₁₋₆alkyl; Het-C(═O)— or -   HetC₁₋₄alkyl; or R^(3c) represents hydrogen; -   or -   B-10) compounds of class B or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein p represents     2; -   or -   B-11) compounds of class B or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein Z represents     C₁₋₆alkanediyl, in particular CH₂ or CH₂—CH₂; -   or -   B-12) compounds of class B or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein R⁸     represents hydrogen; -   or -   B-13) compounds of class B or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein R⁸     represents hydrogen; -   or -   B-14) compounds of class B or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein R⁸     represents halo, C₁₋₄alkyl or C₁₋₄alkyl substituted with hydroxyl;     in particular R⁸ represents halo or C₁₋₄alkyl; -   or -   B-15) compounds of class B or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein R³     represents C₃₋₆cycloalkyl, phenyl, naphtalenyl, 1,3-benzodioxolyl or     a 6-membered aromatic heterocycle containing 1 or 2 N atoms, wherein     said C₃₋₆cyclo-alkyl, phenyl, naphtalenyl, 1,3-benzodioxolyl or     6-membered aromatic heterocycle may optionally be substituted with     at least one substituent, in particular one or two substituents,     preferably each substituent independently selected from hydroxyl;     carboxyl; halo; C₁₋₆alkyl optionally substituted with hydroxy;     polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkylthio;     C₁₋₆alkyloxycarbonyl; amino; mono-or di(C₁₋₄alkyl)amino;     C₁₋₄alkylcarbonylamino; Het; HetC₁₋₄alkyl; -   or -   B-16) compounds of class B or any subgroup thereof as mentioned     hereinbefore as embodiment wherein one or more, preferably all, of     the following restrictions apply: -   a) X represents —NR^(x)—C(═O)—; or —Z—C(═O)—; -   b) the compound of class B is a compound of formula (I″), in     particular a compound of formula (I″) wherein R^(3a) and R^(3b)     represent halo; more in particular chloro; and wherein -   R^(3c) represents hydrogen; -   c) A represents N; -   d) A represents CH; -   e) the dotted line does not represent a bond; -   f) Z represents C₁₋₆alkanediyl; -   g) R¹ represents a 5-membered monocyclic aromatic heterocycle     containing at least 2 heteroatoms, in particular pyrazolyl or     triazolyl; a 6-membered monocyclic aromatic heterocycle; or a     5-membered aromatic heterocycle containing at least 2 heteroatoms     fused with a 5-membered heterocycle; each of said heterocycles     optionally being substituted, in particular substituted with oxo,     C₁₋₆alkyl optionally substituted with aryl-C(═O)—; hydroxyC₁₋₆alkyl     optionally substituted with aryl; C₃₋₆cycloalkyl-NR^(x)—;     Het-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—; aryl; arylC₁₋₄alkyl. -   h) R^(x) represents hydrogen; -   or -   B-17) compounds of class B or any subgroup thereof as mentioned     hereinbefore as embodiment wherein one or more, preferably all, of     the following restrictions apply: -   a) A represents CH or N; -   b) the dotted line does not represents a bond in case A represents a     carbon atom; -   c) X represents —NR^(x)—C(═O)—; —Z—C(═O)—; —Z—NR^(x)—C(═O)—; -   d) Z represents a bivalent radical selected from C₁₋₆alkanediyl; -   e) R^(x) represents hydrogen; -   f) R¹ represents a 5-membered monocyclic heterocycle containing at     least 2 heteroatoms; a 6-membered aromatic monocyclic heterocycle;     or a 5-membered heterocycle containing at least 2 heteroatoms fused     with a 5-membered heterocycle; wherein each of said heterocycles     such as for example pyrazolyl, triazolyl, oxadiazolyl, pyrimidinyl,     imidazopyrazolyl or imidazothienyl, may optionally be substituted     with at least one substituent, in particular one or two     substituents, each substituent independently being selected from     oxo; C₁₋₆alkyl optionally substituted with C₁₋₄alkyloxycarbonyl;     hydroxyC₁₋₆alkyl optionally substituted with aryl; mono-or     di(C₁₋₆alkyl)amino; R⁵R⁴N—C₁₋₆alkyl; Het-NR^(x)—;     arylC₁₋₄alkyl-NR^(x)—; C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl;     aryl; arylC₁₋₄alkyl; aryl-C(═O)—C₁₋₄alkyl; Het; -   g) R³ represents C₃₋₆cycloalkyl, phenyl, naphtalenyl,     1,3-benzodioxolyl, or a 6-membered aromatic heterocycle containing 1     or 2 N atoms, wherein said C₃₋₆cyclo-alkyl, phenyl, naphtalenyl,     1,3-benzodioxolyl or 6-membered aromatic heterocycle may optionally     be substituted with at least one substituent, in particular one or     two substituents, each substituent independently selected from     hydroxyl; carboxyl; halo; C₁₋₆alkyl optionally substituted with     hydroxy; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkylthio;     C₁₋₆alkyloxycarbonyl; mono-or di(C₁₋₄alkyl)amino;     C₁₋₄alkylcarbonylamino; Het; HetC₁₋₄alkyl; -   h) R⁴ represents hydrogen or C₁₋₄alkyl; -   i) R⁵ represents hydrogen or C₁₋₄alkyl; -   j) R⁸ represents hydrogen; -   k) aryl represents phenyl or phenyl substituted with at least one     substituent, in particular one substituent, said substituent being     selected from halo; C₁₋₆alkyl; C₁₋₆alkyloxy; -   l) Het represents a monocyclic non-aromatic or aromatic heterocycle     containing at least one heteroatom selected from O, S, S(═O)_(p) or     N; said monocyclic heterocycle optionally being substituted with     C₁₋₆alkyloxycarbonyl; -   or -   B-181 compounds of class B selected from

A X R¹ R^(q) N

H— N

H— N

H— N

N

N

HOCH₂—

-   including any stereochemically isomeric form thereof; -   a N-oxide thereof, a pharmaceutically acceptable salt thereof or a     solvate thereof.

The next embodiments of the present invention are those combinations of a DGAT inhibitor, more in particular a DGAT1 inhibitor and a PPAR agonist, in particular a PPAR-α agonist, more in particular a fibrate, even more in particular fenofibrate; wherein the DGAT inhibitor is selected from compounds of Class C. Preferred embodiments of compounds of class C are:

-   C-1) compounds of class C having the following formula (D

-   including any stereochemically isomeric form thereof, wherein -   A represents CH or N; -   the dotted line represents an optional bond in case A represents a     carbon atom; -   X represents —NR^(x)—C(═O)—; —Z—C(═O)—; —Z—NR^(x)—C(═O)—; —C(═O)—Z—;     —NR^(x)—C(═O)—Z—; —C(═S)—; —NR^(x)—C(═S)—; —Z—C(═S)—;     —Z—NR^(x)—C(═S)—; —C(═S)—Z—; —NR^(x)—C(═S)—Z—; -   Z represents a bivalent radical selected from C₁₋₆alkanediyl,     C₂₋₆alkenediyl or C₂₋₆alkynediyl; wherein each of said     C₁₋₆alkanediyl, C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally be     substituted with hydroxyl; -   R^(x) represents hydrogen or C₁₋₄alkyl; -   Y represents —C(═O)—NR^(x)— or NR^(x)—C(═O)—; -   R¹ represents C₃₋₆cycloalkyl; aryl¹ or Het¹; -   R² represents C₃₋₆cycloalkyl, phenyl, naphtalenyl,     2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, wherein said     C₃₋₆cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl,     1,3-benzodioxolyl may optionally be substituted with at least one     substituent, in particular one, two, three, four or five     substituents, each substituent independently selected from hydroxyl;     carboxyl; halo; C₁₋₆alkyl optionally substituted with hydroxy;     polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with     C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy;     C₁₋₆alkyloxycarbonyl wherein C₁₋₆alkyl may optionally be substituted     with aryl; cyano; C₁₋₆alkylcarbonyl; nitro; amino; mono-or     di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; R⁴R³N—C(═O)—;     R⁴R³N—C₁₋₆alkyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl;     C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy; arylC₁₋₄alkyl; aryl-C(═O)—;     Het; HetC₁₋₄alkyl; Het-C(═O)—; Het-O—; -   R³ represents hydrogen; C₁₋₄alkyl optionally substituted with     hydroxyl or C₁₋₄alkyloxy; R⁶R⁵N—C₁₋₄alkyl; C₁₋₄alkyloxy; Het; aryl;     R⁶R⁵N—C(═O)—C₁₋₄alkyl; -   R⁴ represents hydrogen or C₁₋₄alkyl; -   R⁵ represents hydrogen; C₁₋₄alkyl; C₁₋₄alkylcarbonyl; -   R⁶ represents hydrogen or C₁₋₄alkyl; or -   R⁵ and R⁶ may be taken together with the nitrogen to which they are     attached to form a saturated monocyclic 5, 6 or 7-membered     heterocycle which may further contain one or more heteroatoms     selected from O, S, S(═O)_(p) or N; and which heterocycle may     optionally be substituted with C₁₋₄alkyl; -   aryl represents phenyl or phenyl substituted with at least one     substituent, in particular one, two, three, four or five     substituents, each substituent independently being selected from     hydroxyl; carboxyl; halo; C₁₋₆alkyl optionally substituted with     C₁₋₄alkyloxy, amino or mono-or di(C₁₋₄alkyl)amino;     polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with     C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;     C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl; mono-or     di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-or     di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; -   aryl¹ represents phenyl, naphthalenyl or fluorenyl; each of said     phenyl, naphthalenyl or fluorenyl optionally substituted with at     least one substituent, in particular one, two, three, four or five     substituents, each substituent independently being selected from     hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl optionally substituted with     aryl-C(═O)—; hydroxyC₁₋₆alkyl optionally substituted with aryl or     aryl-C(═O)—; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted     with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;     C₁₋₆alkyloxy-carbonyl wherein C₁₋₆alkyl may optionally be     substituted with aryl; cyano; aminocarbonyl; mono-or     di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-or     di(C₁₋₆alkyl)amino; C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—;     Het-NR^(x)—; C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;     HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl;     C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;     arylC₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl; Het-C(═O)—; Het-O—; -   Het represents a monocyclic non-aromatic or aromatic heterocycle     containing at least one heteroatom selected from O, S, S(═O)_(p) or     N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle     containing at least one heteroatom selected from O, S, S(═O)_(p) or     N; said monocyclic heterocycle or said bi-or tricyclic heterocycle     optionally being substituted with at least one substituent, in     particular one, two, three, four or five substituents, each     substituent independently being selected from hydroxyl; oxo;     carboxyl; halo; C₁₋₆alkyl optionally substituted with C₁₋₄alkyloxy,     amino or mono-or di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy     optionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio;     polyhaloC₁₋₆alkyloxy; C₁₋₆alkyl-oxycarbonyl; cyano; aminocarbonyl;     mono-or di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino;     mono-or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; -   Het¹ represents a monocyclic non-aromatic or aromatic heterocycle     containing at least one heteroatom selected from O, S, S(═O)_(p) or     N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle     containing at least one heteroatom selected from O, S, S(═O)_(p) or     N; said monocyclic heterocycle or said bi-or tricyclic heterocycle     optionally being substituted with at least one substituent, in     particular one, two, three, four or five substituents, each     substituent independently being selected from hydroxyl; oxo;     carboxyl; halo; C₁₋₆alkyl optionally substituted with aryl-C(═O)—;     hydroxyC₁₋₆alkyl optionally substituted with aryl or aryl-C(═O)—;     polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with     C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;     C₁₋₆alkyloxy-carbonyl wherein C₁₋₆alkyl may optionally be     substituted with aryl; cyano; aminocarbonyl; mono-or     di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-or     di(C₁₋₆alkyl)amino; C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—;     Het-NR^(x)—; C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;     HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl;     C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;     arylC₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl; Het-C(═O)—; Het-O—; -   p represents 1 or 2; -   a N-oxide thereof, a pharmaceutically acceptable salt thereof or a     solvate thereof; -   or -   C-2) compounds of class C or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein X represents     —O—C(═O)—; —NR^(x)—C(═O)—; —Z—C(═O)—; —Z—NR^(x)—C(═O)—; —C(═O)—Z—;     —NR^(x)—C(═O)—Z—; —NR^(x)—C(═S)—; in particular wherein X represents     —NR^(x)—C(═O)—; —Z—C(═O)—; —Z—NR^(x)—C(═O)—; —C(═O)—Z—;     —NR^(x)—C(═O)—Z—; —NR^(x)—C(═S)—; more in particular wherein X     represents —NR^(x)—C(═O)—; —Z—C(═O)—; —Z—NR^(x)—C(═O)—; even more in     particular X represents —NR^(x)—C(═O)— or —Z—NR^(x)—C(═O)—; or X     represents —NR^(x)—C(═O)— or —Z—C(═O)—. Or X represents —O—C(═O)—;     —C(═O)—C(═O)—; —NR^(x)—C(═O)—; —Z—C(═O)—; —Z—NR^(x)—C(═O)—; C(═S)—;     —NR^(x)—C(═S)—; —Z—C(═S)—; —Z—NR^(x)—C(═S)—; -   or -   C-3) compounds of class C or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein A represents     N; -   or -   C-4) compounds of class C or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein A represents     CH, in particular wherein A represents CH and the dotted line does     not represent a bond; -   or -   C-5) compounds of class C or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein R¹     represents aryl¹ or Het¹; in particular optionally substituted     phenyl, optionally substituted fluorenyl or an optionally     substituted monocyclic non-aromatic or aromatic heterocycle     containing at least one heteroatom each independently selected from     O, S, S(═O)_(p) or N, in particular S or N; more in particular     phenyl or fluorenyl, said phenyl or fluorenyl optionally substituted     with one or two substituents, said substituents independently     selected from oxo, carboxyl, halo, C₁₋₆alkyl optionally substituted     with carboxyl or C₁₋₄alkyloxycarbonyl, C₁₋₆alkyloxy,     C₁₋₆alkyloxycarbonyl, amino, aryl, Het or polyhaloC₁₋₆alkyl; or a     4-, 5-or 6-membered non-aromatic or aromatic heterocycle, such as     for example azetidinyl, thiazolidinyl, thiazolyl, pyrrolidinyl,     piperidinyl, said 5-or 6-membered heterocycle optionally substituted     with one or two substituents, said substituents independently     selected from hydroxyl, oxo, C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl, aryl     or Het; -   or -   C-6) compounds of class C or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein R²     represents C₃₋₆cycloalkyl, phenyl, 2,3-dihydro-1,4-benzodioxinyl or     a 6-membered aromatic heterocycle containing 1 or 2 N atoms such as     for example pyridyl, wherein said phenyl or heterocycle are     optionally substituted with one to four substituents, preferably     each substituent independently selected from halo, C₁₋₆alkyl,     C₁₋₆alkyloxy, C₁₋₆alkylthio, C₁₋₆alkyloxycarbonyl, nitro, amino,     mono-or di(C₁₋₄alkyl)amino, aryloxy, R⁴R³N—C₁₋₆alkyl,     Het-C(═O)—C₁₋₄alkyl; -   or -   C-7) compounds of class C or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein the compound     of class C is a compound of formula (I′)

-   wherein R^(3a) and R^(3b) each independently represent hydrogen;     hydroxyl; carboxyl; halo; C₁₋₆alkyl; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy     optionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio;     polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl;     mono-or di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino;     mono-or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; and wherein R^(3c)     represents hydrogen; hydroxyl; carboxyl; halo; C₁₋₆alkyl;     polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with     C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy;     C₁₋₆alkyloxycarbonyl wherein C₁₋₆alkyl may optionally be substituted     with aryl; cyano; C₁₋₆alkylcarbonyl; nitro; amino; mono-or     di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; R⁴R³N—C(═O)—;     R⁴R³N—C₁₋₆alkyl; C₃₋₆cycloalkyl; aryl; aryloxy; arylC₁₋₄alkyl;     aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl;     Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—; -   or -   C-8) compounds of class C or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein the compound     of class C is a compound of formula (I″)

-   wherein R^(3a) and R^(3b) each independently represent hydrogen;     hydroxyl; carboxyl; halo; C₁₋₆alkyl; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy     optionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio;     polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl;     mono-or di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino;     mono-or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; and wherein R^(3c)     represents hydrogen; hydroxyl; carboxyl; halo; C₁₋₆alkyl;     polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with     C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy;     C₁₋₆alkyloxycarbonyl wherein C₁₋₆alkyl may optionally be substituted     with aryl; cyano; C₁₋₆alkylcarbonyl; nitro; amino; mono-or     di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; R⁴R³N—C(═O)—;     R⁴R³N—C₁₋₆alkyl; C₃₋₆cycloalkyl; aryl; aryloxy; arylC₁₋₄alkyl;     aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl;     Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—; -   or -   C-9) compounds of class C or any subgroup thereof as mentioned     hereinbefore as embodiment wherein the compound of formula (I) is a     compound of formula (I′) or (I″) and wherein R^(3a) and R^(3b) each     independently represent halo, C₁₋₆alkyl or C₁₋₆alkyloxy; in     particular halo or C₁₋₆alkyl; more in particular both R^(3a) and     R^(3b) represent halo, more in particular both R^(3a) and R^(3b)     represent chloro; -   or -   C-10) compounds of class C or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein the compound     of formula (I) is a compound of formula (I′) or (I″) and wherein     R^(3c) represents amino; mono-or di(C₁₋₄alkyl)amino; R⁴R³N—C(═O)—;     R⁴R³N—C₁₋₆alkyl; Het-C(═O)— or HetC₁₋₄alkyl; or R^(3c) represents     hydrogen; -   or -   C-11) compounds of class C or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein p represents     2; -   or -   C-12) compounds of class C or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein Z represents     C₁₋₆alkanediyl or C₂₋₆alkenediyl, in particular C₁₋₆alkanediyl, more     in particular —CH₂—; -   or -   C-13) compounds of class C or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein R^(x)     represents hydrogen; -   or -   C-14) compounds of class C or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein Y represents     —NR^(x)—C(═O)—; -   or -   C-15) compounds of class C or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein Y represents     —C(═O)—NR^(x)—; -   or -   C-16) compounds of class C or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein R⁷     represents hydrogen; -   or -   C-17) compounds of class C or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein R⁷     represents halo, C₁₋₄alkyl or C₁₋₄alkyl substituted with hydroxyl;     in particular halo; -   or -   C-18) compounds of class C or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein aryl     represents phenyl or phenyl substituted with halo, C₁₋₆alkyl,     polyhaloC₁₋₆alkyl or C₁₋₆alkyloxycarbonyl; -   or -   C-19) compounds of class C or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein Het     represents a monocyclic non-aromatic or aromatic heterocycle     containing at least one heteroatom each independently selected from     O, S, S(═O)_(p) or N; or a bicyclic non-aromatic or aromatic     heterocycle containing at least one heteroatom each independently     selected from O, S, S(═O)_(p) or N, in particular N; said monocyclic     heterocycle or said bicyclic heterocycle optionally being     substituted with one or two substituents, each substituent     independently being selected from oxo; or C₁₋₆alkyl; -   or -   C-20) compounds of class C or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein one or more,     preferably all, of the following restrictions apply: -   a) X represents —NR^(x)—C(═O)—; —Z—NR^(x)—C(═O)—; or —NR^(x)—C(═S)—; -   b) R¹ represents aryl¹ or Het¹; -   c) R² represents C₃₋₆cycloalkyl, phenyl or     2,3-dihydro-1,4-benzodioxinyl, wherein said phenyl is optionally     substituted with one to four substituents, each substituent     independently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy,     C₁₋₆alkylthio, C₁₋₆alkyloxycarbonyl, nitro, amino, mono-or     di(C₁₋₄alkyl)amino, aryloxy; -   d) A represents N; -   e) A represents CH; -   f) Z represents C₁₋₆alkanediyl or C₂₋₆alkenediyl; -   g) R^(x) represents hydrogen. -   h) aryl¹ represents phenyl or fluorenyl, said phenyl or fluorenyl     optionally substituted with halo, C₁₋₆alkyl or polyhaloC₁₋₆alkyl; -   i) Het¹ represents a 4-, 5-or 6-membered non-aromatic or aromatic     heterocycle, such as for example azetidinyl, thiazolidinyl,     thiazolyl, pyrrolidinyl, piperidinyl, said 5-or 6-membered     heterocycle optionally substituted with hydroxyl, oxo, C₁₋₆alkyl,     C₁₋₆alkyloxycarbonyl, aryl or Het; -   j) Y represents —NR^(x)—C(═O)—; -   k) R⁷ represents hydrogen; -   or -   C-21) compounds of class C or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein one or more,     preferably all, of the following restrictions apply: -   a) A represents CH; -   b) A represents N; -   c) the dotted line represents a bond in case A represents a carbon     atom; -   d) the dotted line doesn't represents a bond in case A represents a     carbon atom; -   e) X represents —O—C(═O)—; —NR^(x)—C(═O)—; —Z—C(═O)—;     —Z—NR^(x)—C(═O)—; —NR^(x)—C(═S)—; -   f) Z represents C₁₋₆alkanediyl; -   g) R^(x) represents hydrogen; -   h) Y represents —C(═O)—NR^(x)— or NR^(x)—C(═O)—; -   i) R¹ represents aryl¹ or Het¹; -   j) R² represents C₃₋₆cycloalkyl, phenyl,     2,3-dihydro-1,4-benzodioxinyl, or a 6-membered aromatic heterocycle     containing 1 or 2 N atoms, wherein said C₃₋₆cycloalkyl, phenyl,     2,3-dihydro-1,4-benzodioxinyl, or 6-membered aromatic heterocycle     containing 1 or 2 N atoms may optionally be substituted with at     least one substituent, in particular one to four substituents, each     substituent independently selected from halo; C₁₋₆alkyl;     C₁₋₆alkyloxy; C₁₋₆alkylthio; C₁₋₆alkyloxycarbonyl; nitro; mono-or     di(C₁₋₄alkyl)amino; R⁴R³N—C₁₋₆alkyl; aryloxy; Het-C(═O)—C₁₋₄alkyl; -   k) R³ represents C₁₋₄alkyl; -   l) R⁴ represents C₁₋₄alkyl; -   m) R⁷ represents hydrogen or halo; -   n) aryl represents phenyl or phenyl substituted with halo;     C₁₋₆alkyl; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxycarbonyl; -   o) aryl¹ represents phenyl or fluorenyl; each of said phenyl or     fluorenyl optionally substituted with one or two substituents, each     substituent independently being selected from oxo; carboxyl; halo;     C₁₋₆alkyl optionally substituted with carboxyl or     C₁₋₄alkyloxycarbonyl; C₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonyl; amino;     aryl; Het; -   p) Het represents a monocyclic non-aromatic or aromatic heterocycle     containing at least one heteroatom each independently selected from     O, S, S(═O)_(p) or N; or a bicyclic non-aromatic or aromatic     heterocycle containing at least one heteroatom each independently     selected from N; said monocyclic heterocycle or said bicyclic     heterocycle optionally being substituted with one or two     substituents, each substituent independently being selected from oxo     or C₁₋₆alkyl; -   q) Het¹ represents a monocyclic non-aromatic or aromatic heterocycle     containing at least one heteroatom each independently selected from     S or N; said monocyclic heterocycle optionally being substituted     with at least one substituent, in particular one or two     substituents, each substituent independently being selected from     hydroxyl; oxo; C₁₋₆alkyl; C₁₋₆alkyloxy-carbonyl; aryl; Het; -   r) p represents 2; -   or -   C-22) compounds of class C selected from

-   including any stereochemically isomeric form thereof; -   a N-oxide thereof, a pharmaceutically acceptable salt thereof or a     solvate thereof; -   or -   C-23) compounds of formula (I), wherein the compound is selected     from -   4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide     (compound 151 Class C); -   4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide     (compound 152 Class C); -   4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide     (compound 147 Class C); -   4-[4-[[2,6-dichloro-4-[[4-(methylsulfonyl)-1-piperazinyl]methyl]phenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide     (compound 150 Class C); -   4-[4-[[4-[(4-acetyl-1-piperazinyl)methyl]-2,6-dichlorophenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide     (compound 149 Class C); -   4-[4-[[2,6-dichloro-4-[(4-ethyl-1-piperazinyl)methyl]phenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide     (compound 148 Class C); -   including any stereochemically isomeric form thereof; -   a N-oxide thereof, a pharmaceutically acceptable salt thereof or a     solvate thereof; -   or -   C-24) compounds of class C or, whenever possible, any subgroup     thereof as mentioned hereinbefore as embodiment wherein R²     represents hydrogen, C₁₋₆alkyl or C₂₋₆alkenyl.

The next embodiments of the present invention are those combinations of a DGAT inhibitor, more in particular a DGAT1 inhibitor and a PPAR agonist, in particular a PPAR-α agonist, more in particular a fibrate, even more in particular fenofibrate; wherein the DGAT inhibitor is selected from compounds of Class D. Preferred embodiments of compounds of class D are:

-   D-1) compounds of class D having the following formula (I)

-   including any stereochemically isomeric form thereof, wherein -   A represents CH or N; -   the dotted line represents an optional bond in case A represents a     carbon atom; -   X represents —C(═O)—; —NR^(x)—C(═O)—; —Z¹—C(═O)—; —Z¹—NR^(x)—C(═O)—;     —C(═O)—Z¹—; —NR^(x)—C(═O)—Z¹—; —S(═O)p-; C(═S)—; —NR^(x)—C(═S)—;     —Z¹—C(═S)—; —Z¹—NR^(x)—C(═S)—; —C(═S)—Z¹—; —NR^(x)—C(═S)—Z¹—; -   Z¹ represents a bivalent radical selected from C₁₋₆alkanediyl,     C₂₋₆alkenediyl or C₂₋₆alkynediyl; wherein each of said     C₁₋₆alkanediyl, C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally be     substituted with hydroxyl; -   Y represents —NR^(x)—C(═O)—Z²—; —NR^(x)—C(═O)—Z²—NR^(y)—;     —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—; —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—O—;     —NR^(x)—C(═O)—Z²—O—; —NR^(x)—C(═O)—Z²—O—C(═O)—;     —NR^(x)—C(═O)—Z²—C(═O)—; —NR^(x)—C(═O)—Z²—C(═O)—O—;     —NR^(x)—C(═O)—O—Z²—C(═O)—; —NR^(x)—C(═O)—O—Z²—C(═O)—O—;     —NR^(x)—C(═O)—O—Z²—O—C(═O)—; —NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—;     —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—; —C(═O)—Z²—; —C(═O)—Z²—O—;     —C(═O)—NR^(x)—Z²—; —C(═O)—NR^(x)—Z²—O—; —C(═O)—NR^(x)—Z²—C(═O)—O—;     —C(═O)—NR^(x)—Z²—O—C(═O)—; —C(═O)—NR^(x)—O—Z²—;     —C(═O)—NR^(x)—Z²—NR^(y)—; —C(═O)—NR^(x)—Z²—NR^(y)—C(═O)—;     —C(═O)—NR^(x)—Z²—NR^(y)—C(═O)—O—; -   Z² represents a bivalent radical selected from C₁₋₆alkanediyl,     C₂₋₆alkenediyl or C₂₋₆alkynediyl; wherein each of said     C₁₋₆alkanediyl, C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally be     substituted with C₁₋₄alkyloxy, C₁₋₄alkylthio, hydroxyl, cyano or     aryl; and wherein two hydrogen atoms attached to the same carbon     atom in the definition of Z² may optionally be replaced by     C₁₋₆alkanediyl; -   R^(x) represents hydrogen or C₁₋₄alkyl; -   R^(y) represents hydrogen; C₁₋₄alkyl optionally substituted with     C₃₋₆cycloalkyl or aryl or Het; C₂₋₄alkenyl; or —S(═O)_(p)-aryl; -   R¹ represents C₁₋₁₂alkyl optionally substituted with cyano,     C₁₋₄alkyloxy, C₁₋₄alkyl-oxyC₁₋₄alkyloxy, C₃₋₆cycloalkyl or aryl;     C₂₋₆alkenyl; C₂₋₆alkynyl; C₃₋₆cycloalkyl; aryl¹; aryl¹C₁₋₆alkyl;     Het¹; or Het¹C₁₋₆alkyl; provided that when Y represents     —NR^(x)—C(═O)—Z²—; —NR^(x)—C(═O)—Z²—NR^(y);     —NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—; —C(═O)—Z²—;     —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—; —C(═O)—NR^(x)—Z²—;     —C(═O)—NR^(x)—O—Z²—; or —C(═O)—NR^(x)—Z²—NR^(y)—; then R¹ may also     represent hydrogen; -   R² represents hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl or R³; -   R³ represents C₃₋₆cycloalkyl, phenyl, naphtalenyl,     2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, wherein said     C₃₋₆cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl,     1,3-benzodioxolyl may optionally be substituted with at least one     substituent, in particular one, two, three, four or five     substituents, each substituent independently selected from hydroxyl;     carboxyl; halo; C₁₋₆alkyl optionally substituted with hydroxy;     polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with     C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy;     C₁₋₆alkyloxycarbonyl wherein C₁₋₆alkyl may optionally be substituted     with aryl; cyano; C₁₋₆alkylcarbonyl; nitro; amino; mono-or     di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; R⁵R⁴N—C(═O)—;     R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl; C₃₋₆cycloalkylC₁₋₄alkyl;     C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy; arylC₁₋₄alkyl; aryl-C(═O)—;     Het; HetC₁₋₄alkyl; Het-C(═O)—; Het-O—; -   R⁴ represents hydrogen; C₁₋₄alkyl optionally substituted with     hydroxyl or C₁₋₄alkyloxy; R⁷R⁶N—C₁₋₄alkyl; C₁₋₄alkyloxy; Het; aryl;     R⁷R⁶N—C(═O)—C₁₋₄alkyl; -   R⁵ represents hydrogen or C₁₋₄alkyl; -   R⁶ represents hydrogen; C₁₋₄alkyl; C₁₋₄alkylcarbonyl; -   R⁷ represents hydrogen or C₁₋₄alkyl; or -   R⁶ and R⁷ may be taken together with the nitrogen to which they are     attached to form a saturated monocyclic 5, 6 or 7-membered     heterocycle which may further contain one or more heteroatoms     selected from O, S, S(═O)_(p) or N; and which heterocycle may     optionally be substituted with C₁₋₄alkyl; -   aryl represents phenyl or phenyl substituted with at least one     substituent, in particular one, two, three, four or five     substituents, each substituent independently being selected from     hydroxyl; carboxyl; halo; C₁₋₆alkyl optionally substituted with     C₁₋₄alkyloxy, amino or mono-or di(C₁₋₄alkyl)amino;     polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with     C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;     C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl; mono-or     di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-or     di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; -   aryl¹ represents phenyl, naphthalenyl or fluorenyl; each of said     phenyl, naphthalenyl or fluorenyl optionally substituted with at     least one substituent, in particular one, two, three, four or five     substituents, each substituent independently being selected from     hydroxyl; oxo; carboxyl; halo; C₁₋₆alkyl optionally substituted with     aryl-C(═O)—; hydroxyC₁₋₆alkyl optionally substituted with aryl or     aryl-C(═O)—; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted     with C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;     C₁₋₆alkyloxy-carbonyl wherein C₁₋₆alkyl may optionally be     substituted with aryl; cyano; aminocarbonyl; mono-or     di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-or     di(C₁₋₆alkyl)amino; C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—;     Het-NR^(x)—; C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;     HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl;     C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;     arylC₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl; Het-C(═O)—; Het-O—; -   Het represents a monocyclic non-aromatic or aromatic heterocycle     containing at least one heteroatom selected from O, S, S(═O)_(p) or     N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle     containing at least one heteroatom selected from O, S, S(═O)_(p) or     N; said monocyclic heterocycle or said bi-or tricyclic heterocycle     optionally being substituted with at least one substituent, in     particular one, two, three, four or five substituents, each     substituent independently being selected from hydroxyl; oxo;     carboxyl; halo; C₁₋₆alkyl optionally substituted with C₁₋₄alkyloxy,     amino or mono-or di(C₁₋₄alkyl)amino; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy     optionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio;     polyhaloC₁₋₆alkyloxy; C₁₋₆alkyl-oxycarbonyl; cyano; aminocarbonyl;     mono-or di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino;     mono-or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; -   Het¹ represents a monocyclic non-aromatic or aromatic heterocycle     containing at least one heteroatom selected from O, S, S(═O)_(p) or     N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle     containing at least one heteroatom selected from O, S, S(═O)_(p) or     N; said monocyclic heterocycle or said bi-or tricyclic heterocycle     optionally being substituted with at least one substituent, in     particular one, two, three, four or five substituents, each     substituent independently being selected from hydroxyl; oxo;     carboxyl; halo; C₁₋₆alkyl optionally substituted with aryl-C(═O)—;     hydroxyC₁₋₆alkyl optionally substituted with aryl or aryl-C(═O)—;     polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with     C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhaloC₁₋₆alkyloxy;     C₁₋₆alkyloxy-carbonyl wherein C₁₋₆alkyl may optionally be     substituted with aryl; cyano; aminocarbonyl; mono-or     di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino; mono-or     di(C₁₋₆alkyl)amino; C₃₋₆cycloalkyl-NR^(x)—; aryl-NR^(x)—;     Het-NR^(x)—; C₃₋₆cycloalkylC₁₋₄alkyl-NR^(x)—; arylC₁₋₄alkyl-NR^(x)—;     HetC₁₋₄alkyl-NR^(x)—; —S(═O)_(p)—C₁₋₄alkyl; C₃₋₆cycloalkyl;     C₃₋₆cycloalkylC₁₋₄alkyl; C₃₋₆cycloalkyl-C(═O)—; aryl; aryloxy;     arylC₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl; Het-C(═O)—; Het-O—; -   p represents 1 or 2; -   a N-oxide thereof, a pharmaceutically acceptable salt thereof or a     solvate thereof; -   or -   D-2) compounds of class D or any subgroup thereof as mentioned     hereinbefore as embodiment wherein X represents —C(═O)—C(═O)—;     —O—C(═O)—; —NR^(x)—C(═O)—; —Z¹—C(═O)—; —Z¹—NR^(x)—C(═O)—;     —C(═O)—Z¹—; —NR^(x)—C(═O)—Z¹—; —S(═O)p-; —NR^(x)—C(═S)—; in     particular X represents —NR^(x)—C(═O)—; —Z¹—C(═O)—;     —Z¹—NR^(x)—C(═O)—; —C(═O)—Z¹—; —NR^(x)—C(═O)—Z¹—; —S(═O)p-;     —NR^(x)—C(═S)—; more in particular X represents —NR^(x)—C(═O)—;     —Z¹—C(═O)—; —C(═O)—Z¹—; —Z¹—NR^(x)—C(═O)—; —NR^(x)—C(═S)— or     —S(═O)p-; even more in particular X represents —NR^(x)—C(═O)— or     —Z¹—NR^(x)—C(═O)—; even more in particular —NR^(x)—C(═O)—; -   or -   D-3) compounds of class D or any subgroup thereof as mentioned     hereinbefore as embodiment wherein A represents N; -   or -   D-4) compounds of class D or any subgroup thereof as mentioned     hereinbefore as embodiment wherein A represents CH, in particular     wherein A represents CH and the dotted line does not represent a     bond; -   or -   D-5) compounds of class D or any subgroup thereof as mentioned     hereinbefore as embodiment wherein R¹ represents C₃₋₆cycloalkyl;     adamantanyl; aryl¹; aryl¹C₁₋₆alkyl; Het¹; or Het¹C₁₋₆alkyl; aryl¹;     in particular aryl¹C₁₋₆alkyl; Het¹; or Het¹C₁₋₆alkyl; more in     particular aryl¹; aryl¹C₁₋₆alkyl; Het¹; or Het¹C₁₋₆alkyl, wherein     said aryl¹ or Het¹ represent phenyl, naphthalenyl, morpholinyl,     piperidinyl, piperazinyl, pyrrolidinyl, furanyl, imidazolyl,     thienyl, pyridyl; each of said cycles representing aryl¹ or Het¹     being optionally substituted with one or two substituents; in     particular with aryl, C₁₋₆alkyl, arylC₁₋₄alkyl, hydroxyl, halo,     polyhaloC₁₋₆alkyl, C₁₋₆alkyloxy, nitro, C₁₋₆alkyloxycarbonyl,     —S(═O)₂—C₁₋₄alkyl; more in particular with aryl, C₁₋₆alkyl,     arylC₁₋₄alkyl, halo, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl,     —S(═O)₂—C₁₋₄alkyl. More in particular R¹ represents aryl¹ wherein     aryl¹ represents preferably optionally substituted phenyl. Even more     in particular R¹ represents phenyl substituted with C₁₋₆alkyloxy,     e.g. methoxy; -   or -   D-6) compounds of class D or any subgroup thereof as mentioned     hereinbefore as embodiment wherein R¹ represents C₁₋₁₂alkyl     optionally substituted with cyano, C₁₋₄alkyloxy,     C₁₋₄alkyl-oxyC₁₋₄alkyloxy, C₃₋₆cycloalkyl or aryl; C₂₋₆alkenyl;     C₂₋₆alkynyl; provided that when Y represents —NR^(x)—C(═O)—Z²—;     —NR^(x)—C(═O)—Z²—NR^(y); —NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—; —C(═O)—Z²—;     —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—; —C(═O)—NR^(x)—Z²—;     —C(═O)—NR^(x)—O—Z²—; or —C(═O)—NR^(x)—Z²—NR^(y)—; then R¹ may also     represent hydrogen; -   or -   D-7) compounds of class D or any subgroup thereof as mentioned     hereinbefore as embodiment wherein R² represents C₁₋₁₂alkyl; in     particular C₁₋₆alkyl; -   or -   D-8) compounds of class D or any subgroup thereof as mentioned     hereinbefore as embodiment wherein R² represents C₁₋₆alkyl or R³; in     particular wherein R² represents R³ and said R³ represents phenyl,     naphthalenyl, 2,3-dihydrobenzofuranyl or 6-membered aromatic     heterocycle containing 1 or 2 N atoms, each of said cycles, in     particular phenyl, being optionally substituted with one to five     substituents, said substituents being in particular halo, C₁₋₆alkyl     optionally substituted with hydroxy, polyhaloC₁₋₆alkyl,     C₁₋₆alkylthio, polyhaloC₁₋₆alkyloxy, carboxyl, hydroxyl,     C₁₋₆alkylcarbonyl, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, nitro,     R⁵R⁴N—C(═O)—, R⁵R⁴N—C₁₋₆alkyl, HetC₁₋₄alkyl, Het-C(═O)—C₁₋₄alkyl,     Het-C(═O)—; said substituents being more in particular halo,     C₁₋₆alkyl optionally substituted with hydroxy, polyhaloC₁₋₆alkyl,     polyhaloC₁₋₆alkyloxy, carboxyl, hydroxyl, C₁₋₆alkylcarbonyl,     C₁₋₆alkyloxy, C₁₋₆alkylthio, C₁₋₆alkyloxycarbonyl, nitro,     R⁵R⁴N—C₁₋₆alkyl, HetC₁₋₄alkyl; more in particular wherein R²     represents phenyl substituted with one, two or three substituents,     preferably three substituents, each substituent being selected from     halo, e.g. chloro, or HetC₁₋₄alkyl, e.g. pyrrolidinylmethyl; -   or -   D-9) compounds of class D or any subgroup thereof as mentioned     hereinbefore as embodiment wherein the compound of class D is a     compound of formula (I′)

-   wherein R^(3a) and R^(3b) each independently represent hydrogen;     hydroxyl; carboxyl; halo; C₁₋₆alkyl; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy     optionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio;     polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl;     mono-or di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino;     mono-or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; and wherein R^(3c)     represents hydrogen; hydroxyl; carboxyl; halo; C₁₋₆alkyl;     polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with     C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy;     C₁₋₆alkyloxycarbonyl wherein C₁₋₆alkyl may optionally be substituted     with aryl; cyano; C₁₋₆alkylcarbonyl; nitro; amino; mono-or     di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; R⁵R⁴N—C(═O)—;     R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl; aryl; aryloxy; arylC₁₋₄alkyl;     aryl-C(═O)—C₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl;     Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—; -   or -   D-10) compounds of class D or any subgroup thereof as mentioned     hereinbefore as embodiment wherein the compound of class D is a     compound of formula (I″)

-   wherein R^(3a) and R^(3b) each independently represent hydrogen;     hydroxyl; carboxyl; halo; C₁₋₆alkyl; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy     optionally substituted with C₁₋₄alkyloxy; C₁₋₆alkylthio;     polyhaloC₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl; cyano; aminocarbonyl;     mono-or di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkylcarbonyl; nitro; amino;     mono-or di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; and wherein R^(3c)     represents hydrogen; hydroxyl; carboxyl; halo; C₁₋₆alkyl;     polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy optionally substituted with     C₁₋₄alkyloxy; C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy;     C₁₋₆alkyloxycarbonyl wherein C₁₋₆alkyl may optionally be substituted     with aryl; cyano; C₁₋₆alkylcarbonyl; nitro; amino; mono-or     di(C₁₋₄alkyl)amino; —S(═O)_(p)—C₁₋₄alkyl; R⁵R⁴N—C(═O)—;     R⁵R⁴N—C₁₋₆alkyl; C₃₋₆cycloalkyl; aryl; aryloxy;     aryl-C(═O)—C₁₋₄alkyl; arylC₁₋₄alkyl; aryl-C(═O)—; Het; HetC₁₋₄alkyl;     Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; Het-O—; -   or -   D-11) compounds of class D or any subgroup thereof as mentioned     hereinbefore as embodiment wherein the compound of class D is a     compound of formula (I′) or (I″) and wherein R^(3a) and R^(3b) each     independently represent halo, C₁₋₆alkyl or C₁₋₆alkyloxy; in     particular halo or C₁₋₆alkyl; more in particular both R^(3a) and     R^(3b) represent halo, more in particular both R^(3a) and R^(3b)     represent chloro; -   or -   D-12) compounds of class D or any subgroup thereof as mentioned     hereinbefore as embodiment wherein the compound of formula (I) is a     compound of formula (I′) or (I″) and wherein R^(3c) represents     amino; mono-or di(C₁₋₄alkyl)amino; R⁵R⁴N—C(═O)—; R⁵R⁴N—C₁₋₆alkyl;     Het-C(═O)—; Het-C(═O)—C₁₋₄alkyl or HetC₁₋₄alkyl; or R^(3c)     represents hydrogen; more in particular wherein R^(3c) represents     amino; mono-or di(C₁₋₄alkyl)amino; R⁵R⁴N—C(═O)—; R⁵R⁴N—C₁₋₆alkyl;     Het-C(═O)— or HetC₁₋₄alkyl; or R^(3c) represents hydrogen; even more     in particular wherein R^(3c) represents HetC₁₋₄alkyl, e.g.     pyrrolidinylmethyl; -   or -   D-13) compounds of class D or any subgroup thereof as mentioned     hereinbefore as embodiment wherein p represents 2; -   or -   D-14) compounds of class D or any subgroup thereof as mentioned     hereinbefore as embodiment wherein Y represents —NR^(x)—C(═O)—Z²—;     —NR^(x)—C(═O)—Z²—NR^(y); —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—O—;     —NR^(x)—C(═O)—Z²—O—C(═O)—; —NR^(x)—C(═O)—Z²—C(═O)—O—;     —NR^(x)—C(═O)—O—Z²—C(═O)—O—; —NR^(x)—C(═O)—O—Z²—O—C(═O)—;     —NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—;     —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—; —C(═O)—NR^(x)—Z²—;     —C(═O)—NR^(x)—Z²—O—; —C(═O)—NR^(x)—Z²—C(═O)—O—;     —C(═O)—NR^(x)—Z²—O—C(═O)—; —C(═O)—NR^(x)—O—Z²—;     —C(═O)—NR^(x)—Z²—NR^(y)—; —C(═O)—NR^(x)—Z²—NR^(y)—C(═O)—;     —C(═O)—NR^(x)—Z²—NR^(y)—C(═O)—O—; or wherein Y represents     NR^(x)—C(═O)—Z²—; —NR^(x)—C(═O)—Z²—NR^(y);     —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—; —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—O—;     —NR^(x)—C(═O)—Z²—O—; —NR^(x)—C(═O)—Z²—C(═O)—O—;     —NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—;     —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—; —C(═O)—Z²—; or wherein Y     represents NR^(x)—C(═O)—Z²— or —NR^(x)—C(═O)—Z²—NR^(y); or wherein Y     represents —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—O— or     —NR^(x)—C(═O)—Z²—C(═O)—O—. More in particular Y represents     —NR^(x)—C(═O)—Z²—; -   or -   D-15) compounds of class D or any subgroup thereof as mentioned     hereinbefore as embodiment wherein Y represents NR^(x)—C(═O)—Z²—;     —NR^(x)—C(═O)—Z²—NR^(y)—; —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—;     —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—O—; —NR^(x)—C(═O)—Z²—O—;     —NR^(x)—C(═O)—Z²—O—C(═O)—; —NR^(x)—C(═O)—Z²—C(═O)—O—;     —NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—;     —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—; —C(═O)—Z²—;     —C(═O)—NR^(x)—Z²—; —C(═O)—NR^(x)—Z²—O—; -   or -   D-16) compounds of class D or any subgroup thereof as mentioned     hereinbefore as embodiment wherein Z² represents C₁₋₆alkanediyl or     C₂₋₆alkenediyl; in particular C₁₋₆alkanediyl; more in particular     methylene; -   or -   D-17) compounds of class D or any subgroup thereof as mentioned     hereinbefore as embodiment wherein Z¹ represents C₁₋₆alkanediyl,     optionally substituted with hydroxyl or amino, or wherein two     hydrogen atoms attached to the same carbon atom in C₁₋₆alkanediyl     may optionally be replaced by C₁₋₆alkanediyl; in particular wherein     Z¹ represents C₁₋₆alkanediyl; -   or -   D-18) compounds of class D or any subgroup thereof as mentioned     hereinbefore as embodiment wherein R^(x) represents hydrogen; -   or -   D-19) compounds of class D or any subgroup thereof as mentioned     hereinbefore as embodiment wherein R^(y) represents hydrogen or     C₁₋₄alkyl or C₂₋₄alkenyl or —S(═O)_(p)-aryl; -   or -   D-20) compounds of class D or any subgroup thereof as mentioned     hereinbefore as embodiment wherein R⁸ represents hydrogen; -   or -   D-21) compounds of class D or any subgroup thereof as mentioned     hereinbefore as embodiment wherein R⁸ represents halo, C₁₋₄alkyl or     C₁₋₄alkyl substituted with hydroxyl; -   or -   D-22) compounds of class D or any subgroup thereof as mentioned     hereinbefore as embodiment wherein aryl represents phenyl or phenyl     substituted with one or two substituents, preferably each     substituent independently selected from halo, C₁₋₆alkyl,     polyhaloC₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl or nitro; -   or -   D-23) compounds of class D or any subgroup thereof as mentioned     hereinbefore as embodiment wherein Het¹ represents a monocyclic     non-aromatic or aromatic heterocycle or a bicyclic non-aromatic     heterocycle, each of said cycles may optionally be substituted. In     particular Het¹ represents morpholinyl, pyrrolidinyl, piperazinyl,     homopiperazinyl, piperidinyl, furanyl, imidazolyl, thienyl, pyridyl,     1,3-benzodioxolyl, tetrahydropyranyl, each of said heterocycles     optionally being substituted with one or two substituents,     preferably each substituent independently being selected from halo,     C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl, —S(═O)_(p)—C₁₋₄alkyl, aryl,     arylC₁₋₄alkyl, polyhaloC₁₋₆alkyl, C₁₋₆alkyloxy, nitro; more     preferably each substituent independently being selected from halo,     C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl, —S(═O)_(p)—C₁₋₄alkyl, aryl,     arylC₁₋₄alkyl; -   or -   D-24) compounds of class D or any subgroup thereof as mentioned     hereinbefore as embodiment wherein aryl¹ represents phenyl,     naphthalenyl or phenyl substituted with one or two substituents,     preferably each substituent independently being selected from     hydroxyl, halo, C₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl or     Het; -   or -   D-25) compounds of class D or any subgroup thereof as mentioned     hereinbefore as embodiment wherein Het is a monocyclic non-aromatic     or aromatic heterocycle, each of said heterocycles may optionally be     substituted. In particular, Het is piperidinyl, pyrrolidinyl,     piperazinyl, pyridyl, morpholinyl, each of said heterocycles     optionally being substituted with one substituent, preferably the     substituent is selected from C₁₋₆alkyl, C₁₋₆alkyl substituted with     C₁₋₄alkyloxy, —S(═O)_(p)—C₁₋₄alkyl, C₁₋₆alkylcarbonyl; -   or -   D-26) compounds of class D or any subgroup thereof as mentioned     hereinbefore as embodiment wherein one or more, preferably all, of     the following restrictions apply: -   a) X represents —NR^(x)—C(═O)—; —Z¹—C(═O)—; —Z¹—NR^(x)—C(═O)—;     —C(═O)—Z¹—; —S(═O)p-; —NR^(x)—C(═S)—; -   b) R² represents C₁₋₆alkyl or R³, with R³ representing phenyl,     naphthalenyl or 1,3-benzodioxolyl, each of said cycles being     optionally substituted with one to five substituents, said     substituents being in particular halo, C₁₋₆alkyl optionally     substituted with hydroxy, polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy,     carboxyl, hydroxyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxy, C₁₋₆alkylthio,     C₁₋₆alkyloxycarbonyl, nitro, R⁵R⁴N—C₁₋₆alkyl, HetC₁₋₄alkyl. -   c) A represents N; -   d) A represents CH; -   e) Y represents NR^(x)—C(═O)—Z²—; —NR^(x)—C(═O)—Z²—NR^(y);     —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—; —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—O—;     —NR^(x)—C(═O)—Z²—O—; —NR^(x)—C(═O)—Z²—C(═O)—O—;     —NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—;     —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—; —C(═O)—Z²—; -   f) Z¹ represents C₁₋₆alkanediyl optionally substituted with hydroxy; -   g) R^(y) represents hydrogen; C₁₋₄alkyl optionally substituted with     C₃₋₆cycloalkyl or aryl; C₂₋₄alkenyl; or —S(═O)_(p)-aryl; -   h) aryl¹ represents phenyl, said phenyl optionally substituted with     C₁₋₆alkyl, halo, polyhaloC₁₋₆alkyl, C₁₋₆alkyloxy, nitro,     C₁₋₆alkyloxycarbonyl; -   i) Het¹ represents a 5-or 6-membered non-aromatic or aromatic     heterocycle, such as for example morpholinyl, piperidinyl,     piperazinyl, pyrrolidinyl, furanyl, imidazolyl, thienyl, pyridyl,     said 5-or 6-membered heterocycle optionally substituted with aryl,     C₁₋₆alkyl, arylC₁₋₆alkyl, halo, polyhaloC₁₋₆alkyl,     C₁₋₆alkyloxycarbonyl, —S(═O)₂—C₁₋₄alkyl; -   or -   D-27) compounds of class D having the following formula

-   wherein one or more, preferably all, of the following restrictions     apply: -   a) A represents CH or N; -   b) X represents —O—C(═O)—; —C(═O)—C(═O)—; —NR^(x)—C(═O)—;     —Z¹—C(═O)—; —Z¹—NR^(x)—C(═O)—; —C(═O)—Z¹—; —S(═O)p-; —NR^(x)—C(═S)—; -   c) Z¹ represents C₁₋₆alkanediyl; wherein said C₁₋₆alkanediyl may     optionally be substituted with hydroxyl or amino; and wherein two     hydrogen atoms attached to the same carbon atom in C₁₋₆alkanediyl     may optionally be replaced by C₁₋₆alkanediyl; -   d) Y represents NR^(x)—C(═O)—Z²—; —NR^(x)—C(═O)—Z²—NR^(y)—;     —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—; —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—O—;     —NR^(x)—C(═O)—Z²—O—; —NR^(x)—C(═O)—Z²—O—C(═O)—;     —NR^(x)—C(═O)—Z²—C(═O)—O—; —NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—;     —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—; —C(═O)—Z²—;     —C(═O)—NR^(x)—Z²—; —C(═O)—NR^(x)—Z²—O—; -   e) Z² represents a bivalent radical selected from C₁₋₆alkanediyl,     C₂₋₆alkenediyl or C₂₋₆alkynediyl; wherein each of said     C₁₋₆alkanediyl, C₂₋₆alkenediyl or C₂₋₆alkynediyl may optionally be     substituted with C₁₋₄alkyloxy, C₁₋₄alkylthio, hydroxyl, cyano or     aryl; and wherein two hydrogen atoms attached to the same carbon     atom in the definition of Z² may optionally be replaced by     C₁₋₆alkanediyl; -   f) R^(x) represents hydrogen or C₁₋₄alkyl; -   g) R^(y) represents hydrogen; C₁₋₄alkyl; C₂₋₄alkenyl; or     —S(═O)_(p)-aryl; -   h) R¹ represents C₁₋₁₂alkyl optionally substituted with cyano,     C₁₋₄alkyloxy, C₁₋₄alkyl-oxyC₁₋₄alkyloxy, C₃₋₆cycloalkyl or aryl;     C₂₋₆alkenyl; C₂₋₆alkynyl; C₃₋₆cycloalkyl; adamantanyl; aryl¹; Het¹;     or Het¹C₁₋₆alkyl; provided that when Y represents —NR^(x)—C(═O)—Z²—;     —NR^(x)—C(═O)—Z²—NR^(y); —NR^(x)—C(═O)—Z²—C(═O)—NR^(y)—; —C(═O)—Z²—;     —NR^(x)—C(═O)—Z²—NR^(y)—C(═O)—NR^(y)—; —C(═O)—NR^(x)—Z²—;     —C(═O)—NR^(x)—O—Z²—; or —C(═O)—NR^(x)—Z²—NR^(y)—; then R¹ may also     represent hydrogen; -   i) R² represents C₁₋₁₂alkyl or R³; -   j) R³ represents phenyl, naphtalenyl, 2,3-dihydrobenzofuranyl or a     6-membered aromatic heterocycle containing 1 or 2 N atoms, wherein     said phenyl, naphtalenyl, 2,3-dihydrobenzofuranyl or 6-membered     aromatic heterocycle containing 1 or 2 N atoms may optionally be     substituted with at least one substituent, in particular one, two,     three, four or five substituents, each substituent independently     selected from hydroxyl; carboxyl; halo; C₁₋₆alkyl optionally     substituted with hydroxy; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy;     C₁₋₆alkylthio; polyhalo-C₁₋₆alkyloxy; C₁₋₆alkyloxycarbonyl;     C₁₋₆alkylcarbonyl; nitro; R⁵R⁴N—C(═O)—; R⁵R⁴N—C₁₋₆alkyl;     HetC₁₋₄alkyl; Het-C(═O)—C₁₋₄alkyl; Het-C(═O)—; -   k) R⁴ represents hydrogen; C₁₋₄alkyl optionally substituted with     hydroxyl or C₁₋₄alkyloxy; R⁷R⁶N—C₁₋₄alkyl; Het-C₁₋₄alkyl;     R⁷R⁶N—C(═O)—C₁₋₄alkyl; -   l) R⁵ represents hydrogen or C₁₋₄alkyl; -   m) R⁶ represents C₁₋₄alkyl or C₁₋₄alkylcarbonyl; -   n) R⁷ represents hydrogen or C₁₋₄alkyl; or -   o) R⁶ and R⁷ may be taken together with the nitrogen to which they     are attached to form a saturated monocyclic 5, 6 or 7-membered     heterocycle which may further contain one or more heteroatoms each     independently selected from O or N; -   p) R⁸ represents hydrogen, halo, C₁₋₄alkyl substituted with     hydroxyl; -   q) aryl represents phenyl or phenyl substituted with at least one     substituent, in particular one or two substituents, each substituent     independently being selected from halo; C₁₋₆alkyl;     polyhaloC₁₋₆alkyl; C₁₋₆alkyloxy; nitro; -   r) aryl¹ represents phenyl or naphthalenyl; wherein phenyl may     optionally be substituted with one or two substituents, each     substituent independently being selected from hydroxyl; halo;     C₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkyloxy-carbonyl or Het; -   s) Het represents a monocyclic non-aromatic or aromatic heterocycle     containing at least one heteroatom each independently selected from     O, S, S(═O)_(p) or N, in particular N; said monocyclic heterocycle     optionally being substituted with one substituent, said substituent     being selected from C₁₋₆alkyl optionally substituted with     C₁₋₄alkyloxy; C₁₋₆alkylcarbonyl or —S(═O)_(p)—C₁₋₄alkyl; -   t) Het¹ represents a monocyclic non-aromatic or aromatic heterocycle     containing at least one heteroatom each independently selected from     O, S, S(═O)_(p) or N, in particular N, O or S; or a bicyclic     non-aromatic heterocycle containing at least one heteroatom each     independently selected from O, S, S(═O)_(p) or N, in particular O;     said monocyclic heterocycle or said bicyclic heterocycle optionally     being substituted with one or two substituents, each substituent     independently being selected from halo; C₁₋₆alkyl;     C₁₋₆alkyloxy-carbonyl; —S(═O)_(p)—C₁₋₄alkyl; aryl; or arylC₁₋₄alkyl; -   u) p represents 2; -   or -   D-28) compounds of class D selected from

-   including any stereochemically isomeric form thereof; -   a N-oxide thereof, a pharmaceutically acceptable salt thereof or a     solvate thereof. -   or -   D-29) compounds of class D selected from

-   including any stereochemically isomeric form thereof; -   a N-oxide thereof, a pharmaceutically acceptable salt thereof or a     solvate thereof. -   or -   D-30) compounds of class D selected from: -   N-[4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]phenyl]-4-methoxy-benzeneacetamide     (compound 355 Class D); -   4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide     (compound 354 Class D); -   4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide     (compound 356 Class D); -   4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide     (compound 358 Class D); -   4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide     (compound 353 Class D); -   4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide     (compound 357 Class D); -   4-[4-[[2,6-dichloro-4-[(4-ethyl-1-piperazinyl)methyl]phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide     (compound 360 Class D); -   4-[4-[[2,6-dichloro-4-[(4-ethyl-1-piperazinyl)methyl]phenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide     (compound 359 Class D); -   4-[4-[[2,6-dichloro-4-[[4-(methylsulfonyl)-1-piperazinyl]methyl]phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide     (compound 364 Class D); -   4-[4-[[4-[(4-acetyl-1-piperazinyl)methyl]-2,6-dichlorophenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide     (compound 361 Class D); -   4-[4-[[2,6-dichloro-4-[[4-(methylsulfonyl)-1-piperazinyl]methyl]phenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide     (compound 363 Class D); -   4-[4-[[4-[(4-acetyl-1-piperazinyl)methyl]-2,6-dichlorophenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide     (compound 362 Class D); -   N-[4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazinyl]phenyl]-4-methoxy-benzeneacetamide     (compound 352 Class D); -   N-[4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]phenyl]-4-methoxy-benzeneacetamide     (compound 351 Class D); -   4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide     (compound 267 Class D); -   including any stereochemically isomeric form thereof; -   a N-oxide thereof, a pharmaceutically acceptable salt thereof or a     solvate thereof.

In an embodiment, the present invention also relates to a combination of

-   including any stereochemically isomeric form thereof; -   a N-oxide thereof, a pharmaceutically acceptable salt thereof or a     solvate thereof; and fenofibrate.

In an embodiment, the present invention also relates to a combination of 4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide (compound 358 Class D), including any stereochemically isomeric form thereof; a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof;

-   and fenofibrate.     General Preparation     I) Class A Compounds

The general preparation of the compounds of Class A is described in WO2008/148851, the content of which is enclosed by reference in the present application.

II) Class B Compounds

The general preparation of the compounds of Class B is described in WO2008/148840, the content of which is enclosed by reference in the present application.

III) Class C Compounds

The general preparation of the compounds of Class C is described in WO2008/148849, the content of which is enclosed by reference in the present application.

IV) Class D Compounds

The general preparation of the compounds of Class D is described in WO2008/148868, the content of which is enclosed by reference in the present application.

In addition to the general procedures described in WO2008/148868, intermediates of Class D of formula (XI) can also be prepared from an intermediate of formula (LXIV) in the presence of an acid such as, for example, an HCl solution. The reaction may be performed in the presence of a suitable solvent such as, for example, dioxane. Intermediates of formula (LXIV) wherein R² contains Het-C₁₋₄alkyl as substituent (Het is defined as a saturated N-containing heterocycle such as, for example, pyrrollidinyl) and wherein X₁ is a direct bond, said intermediates being represented by formula (LXIV-a) can be prepared by reacting an intermediate of formula (LXV) in het presence of a saturated N-containing heterocycle such as, for example, pyrrolidine, and water. Intermediates of formula (LXV) can be prepared by reacting an intermediate of formula (LXII) wherein R² contains Het-C₁₋₄alkyl as substituent, hereby named (LXII-a), in the presence of tetrabromomethane and a catalyst such as, for example, triphenylphosphine. This reaction can be performed in a suitable solvent such as, for example, DCM.

Pharmacological Part

As already indicated above, the present invention relates to the use of a drug combination comprising a DGAT inhibitor and a PPAR agonist or a prodrug thereof, as a medicament.

In particular, the present invention relates to the use of a drug combination comprising a DGAT inhibitor and a PPAR-α agonist or a prodrug thereof, as a medicament.

In particular, the present invention relates to the use of a drug combination comprising a DGAT1 inhibitor and a PPAR-α agonist or a prodrug thereof, as a medicament.

In particular, the combinations according to the present invention are suitable for reducing food intake, for reducing weight, for suppressing appetite, for inducing satiety; or for the treatment or prevention, in particular treatment, of metabolic disorders, such as obesity and/or obesity related disorders (including, but not limited to, peripheral vascular disease, cardiac failure, myocardial ischaemia, cerebral ischaemia, cardiac myopathies), diabetes, in particular type II diabetes mellitus, and/or complications arising therefrom (such as retinopathy, neuropathy, nephropathy), syndrome X, insulin resistance, impaired glucose tolerance, conditions of impaired fasting glucose, hypoglycemia, hyperglycemia, hyperuricemia, hyperinsulinemia, pancreatitis, hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed dyslipidemia, hypertriglyceridemia, nonalcoholic fatty liver disease, fatty liver, increased mesenteric fat, non-alcoholic steatohepatitis, liver fibrosis, metabolic acidosis, ketosis, dysmetabolic syndrome; dermatological conditions such as acne, psoriasis; cardiovascular diseases, such as atherosclerosis, arteriosclerosis, acute heart failure, congestive heart failure, coronary artery disease, cardiomyopathy, myocardial infarction, angina pectoris, hypertension, hypotension, stroke, ischemia, ischemic reperfusion injury, aneurysm, restenosis or vascular stenosis; alzheimer's disease; neoplastic diseases, such as solid tumors, skin cancer, melanoma, lymphoma or endothelial cancers, e.g., breast cancer, lung cancer, colorectal cancer, stomach cancer, other cancers of the gastrointestinal tract (e.g., esophageal cancer or pancreatic cancer), prostate cancer, kidney cancer, liver cancer, bladder cancer, cervical cancer, uterine cancer, testicular cancer or ovarian cancer.

In an embodiment, the combinations according to the present invention are suitable for reducing food intake, for reducing weight, for suppressing appetite, for inducing satiety; or for the treatment or prevention, in particular treatment, of metabolic disorders, such as obesity and/or obesity related disorders (including, but not limited to, peripheral vascular disease, cardiac failure, myocardial ischaemia, cerebral ischaemia, cardiac myopathies), diabetes, in particular type II diabetes mellitus, and/or complications arising therefrom (such as retinopathy, neuropathy, nephropathy), syndrome X, insulin resistance, impaired glucose tolerance, conditions of impaired fasting glucose, hypoglycemia, hyperglycemia, hyperuricemia, hyperinsulinemia, pancreatitis, hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed dyslipidemia, hypertriglyceridemia, nonalcoholic fatty liver disease, fatty liver, increased mesenteric fat, non-alcoholic steatohepatitis, liver fibrosis, metabolic acidosis, ketosis, dysmetabolic syndrome; dermatological conditions such as acne, psoriasis; cardiovascular diseases, such as atherosclerosis, arteriosclerosis, acute heart failure, congestive heart failure, coronary artery disease, cardiomyopathy, myocardial infarction, angina pectoris, hypertension, hypotension, stroke, ischemia, ischemic reperfusion injury, aneurysm, restenosis or vascular stenosis.

In an embodiment, the combinations according to the present invention are suitable for reducing food intake, for reducing weight, for suppressing appetite, for inducing satiety; or for the treatment or prevention, in particular treatment, of obesity and/or obesity related disorders, hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed dyslipidemia, hypertriglyceridemia, fatty liver, nonalcoholic fatty liver disease, liver fibrosis, non-alcoholic steatohepatitis or diabetes.

In an embodiment, the combinations according to the present invention are suitable for reducing food intake, for reducing weight, for suppressing appetite, for inducing satiety; for the treatment or prevention of obesity and/or obesity related disorders, obesity or cardiovascular diseases.

In an embodiment, said obesity related disorder is selected from peripheral vascular disease, cardiac failure, myocardial ischaemia, cerebral ischaemia or cardiac myopathies.

In an embodiment, the combinations according to the present invention are suitable for reducing food intake and/or for reducing weight.

In an embodiment, the combinations according to the present invention are suitable for reducing food intake.

In an embodiment, the combinations according to the present invention are suitable for the treatment of said diseases or conditions.

In an embodiment, the combinations according to the present invention are suitable for use in the treatment or prevention, in particular treatment, of said diseases or conditions.

In an embodiment, the combinations according to the present invention are suitable for the manufacture of a medicament; in particular a medicament for the treatment or prevention, in particular the treatment, of the diseases or conditions mentioned hereinbefore.

The present invention also relates to a product containing a) a DGAT inhibitor, in particular a DGAT1 inhibitor, more in particular a compound of Class A, Class B, Class C or Class D, and (b) an agonist of peroxisome proliferators-activator receptor or a prodrug thereof such as for example fenofibrate, as a combined preparation for simultaneous, separate or sequential use in the treatment of a disease which can benefit from an elevated level of GLP-1 or DGAT inhibition, such as for example diabetes, in particular type II diabetes mellitus, obesity, for suppressing appetite, inducing satiety or for reducing food intake.

In view of the utility of the combinations of the present invention, there is provided a method of treating warm-blooded animals, including humans, suffering from or a method of preventing warm-blooded animals, including humans, to suffer from any one of the diseases or conditions mentioned hereinbefore.

Said methods comprise the administration, i.e. the systemic or topical administration, preferably oral administration, of an effective amount of an above mentioned combination to warm-blooded animals, including humans.

Those of skill in the treatment of such diseases could determine the effective therapeutic daily amount from the test results presented hereinafter. An effective therapeutic daily amount of a combination of PPAR agonist (or prodrug thereof)/DGAT inhibitor would be from about 0.01 mg/kg to 250 mg/kg body weight, preferably from 0.01 mg/kg to 50 mg/kg body weight, more preferably from about 0.01 mg/kg to about 10 mg/kg, even more preferably from about 0.05 mg/kg to about 1 mg/kg body weight. The amount of a compound according to the present invention, also referred to here as the active ingredient, which is required to achieve a therapeutically effect will of course, vary on case-by-case basis, for example with the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder or disease being treated.

A method of treatment may also include administering the active ingredient on a regimen of between one and four intakes per day. In these methods of treatment the compounds according to the invention are preferably formulated prior to administration. As described herein below, suitable pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients.

In an embodiment, the present invention also relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier, and as active ingredient a therapeutically effective amount of the combinations mentioned hereinbefore or hereinafter.

The combinations of the present invention may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular combination, as the active ingredient, is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.

The combinations of the present invention may also be administered via inhalation or insufflation by means of methods and formulations employed in the art for administration via this way. Thus, in general the compounds of the present invention may be administered to the lungs in the form of a solution, a suspension or a dry powder. Any system developed for the delivery of solutions, suspensions or dry powders via oral or nasal inhalation or insufflation are suitable for the administration of the present compounds.

The combinations of the present invention may also be topically administered in the form of drops, in particular eye drops. Said eye drops may be in the form of a solution or a suspension. Any system developed for the delivery of solutions or suspensions as eye drops are suitable for the administration of the present compounds.

It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage.

Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.

The exact dosage and frequency of administration depends on the particular combination of the present invention used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the combinations of the instant invention.

Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% by weight, more preferably from 0.1 to 70% by weight, even more preferably from 0.1 to 50% by weight of the combination of PPAR agonist/DGAT inhibitor, and, from 1 to 99.95% by weight, more preferably from 30 to 99.9% by weight, even more preferably from 50 to 99.9% by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.

In all previous embodiments, the different drugs of a combination or product may be combined in a single preparation together with pharmaceutically acceptable carriers or they may be present in a separate preparation together with pharmaceutically acceptable carriers.

As already indicated above, the present invention also relates to the use of the novel DGAT inhibitors of group Q, in particular DGAT1 inhibitors of group Q, to elevate levels of one or more satiety hormones, in particular GLP-1 levels. The present invention also relates to the use of a DGAT inhibitor of group Q, in particular a novel DGAT1 inhibitor of group Q, for the manufacture of a medicament for the prevention or the treatment, in particular for the treatment, of a disease which can benefit from an elevated level of one or more satiety hormones, in particular a disease which can benefit from an elevated GLP-1 level. In particular, GLP-1 levels are elevated in plasma or in portal blood, more in particular in plasma. By elevated GLP-1 levels, e.g. elevated GLP-1 plasma level or an elevated GLP-1 level in portal blood, it is meant that the GLP-1 level of a subject having taken a DGAT1 inhibitor is elevated or increased compared to the subject under the same conditions but not having taken the DGAT1 inhibitor. In particular GLP-1 levels are elevated in fasting conditions or postprandial, more in particular postprandial.

Therapeutic uses for a compound which elevates GLP-1 level include, but are not limited to, improving learning, enhancing neuro-protection, and/or alleviating a symptom of a disease or disorder of the central nervous system, e.g., through modulation of neurogenesis, and e.g., Parkinson's Disease, Alzheimer's Disease, Huntington's Disease, ALS, stroke, hemorrhage, cerebrovascular accident, ADD, and neuropsychiatric syndromes; converting liver stem/progenitor cells into functional pancreatic cells; preventing beta-cell deterioration and stimulation of beta-cell proliferation; treating pancreatitis; treating obesity; suppressing appetite and inducing satiety; treating irritable bowel syndrome or inflammatory bowel disease such as Crohn's disease and ulcerative colitis; reducing the morbidity and/or mortality associated with myocardial infarction and stroke; treating acute coronary syndrome characterized by an absence of Q-wave myocardial infarction; attenuating post-surgical catabolic changes; treating hibernating myocardium or diabetic cardiomyopathy; suppressing plasma blood levels of norepinepherine; increasing urinary sodium excretion, decreasing urinary potassium concentration; treating conditions or disorders associated with toxic hypervolemia, e.g., renal failure, congestive heart failure, nephrotic syndrome, cirrhosis, pulmonary edema, and hypertension; inducing an inotropic response and increasing cardiac contractility; treating polycystic ovary syndrome; treating respiratory distress; improving nutrition via a non-alimentary route, i.e., via intravenous, subcutaneous, intramuscular, peritoneal, or other injection or infusion; treating nephropathy; treating left ventricular systolic dysfunction, e.g., with abnormal left ventricular ejection fraction; inhibiting antro-duodenal motility, e.g., for the treatment or prevention of gastrointestinal disorders such as diarrhea, postoperative dumping syndrome and irritable bowel syndrome, and as premedication in endoscopic procedures; treating critical illness polyneuropathy (CIPN) and systemic inflammatory response syndrome (SIRS); modulating triglyceride levels and treating dyslipidemia; treating organ tissue injury (e.g. brain tissue injury) caused by reperfusion of blood flow following ischemia; improving the function of ischemic and reperfused brain tissue; treating coronary heart disease risk factor (CHDRF) syndrome. Further diseases which can benefit from an elevated GLP-1 level, include, but are not limited to, ischemic myocardial stunning; ishemic/reperfusion injury; acute myocardial infarction; left ventricular dysfunction; vascular disease; neuropathy, including periphere sensoric neuropathy associated with type II diabetes; bone-related disorders, including osteoporosis, obesity, diabetes. Because of the effect on GLP-1, the DGAT inhibitors of group Q can also be used to provide cardioprotection.

References supporting the above indications include Experimental Neurology, Vol. 203(2), pp 293-301 (2007); U.S. Pat. No. 7,186,683; J. Pharm. Exp. Ther. vol. 312, No. 1, pp 303-308 (2005); Diabetes, vol. 54, pp 146-151 (2005); US2007/0021339, which are incorporated herein by reference.

In view of the DGAT inhibitory activity, in particular the DGAT1 inhibitory activity, the present novel compounds of group Q can be used as a medicament. In particular, the present invention relates to a compound of group Q for use as a medicament, in particular for use as a medicament for the prevention or the treatment of a disease which can benefit from an elevated GLP-1 level. In particular, the present invention also relates to the use of a compound of group Q for the manufacture of a medicament for the prevention or the treatment of a disease which can benefit from an elevated GLP-1 level, such as the diseases and disorders mentioned above.

In view of the DGAT inhibitory activity of the compounds of group Q, there is provided a method of treating a warm-blooded mammal, including a human, suffering from or a method of preventing a warm-blooded mammal, including a human, to suffer from a disease which can benefit from an elevated level of GLP-1, in particular a method of treating a warm-blooded mammal, including a human, suffering from a disease which can benefit from an elevated level of GLP-1. Said methods comprise the administration of an effective amount of a compound of group Q to a warm-blooded mammal, including a human.

In view of the DGAT inhibitory activity, in particular the DGAT1 inhibitory activity, the present invention also relates to a compound of group Q for use as a medicament, in particular for use as a medicament for the prevention or the treatment of a diseases which can benefit from inhibition of DGAT, in particular DGAT1.

The invention also relates to a compound of group Q for the prevention or the treatment of a disease or disorder which can benefit from inhibition of DGAT, in particular DGAT1. Diseases or disorders which can benefit from inhibition of DGAT, in particular DGAT1 include, but are not limited to metabolic disorders, such as obesity and/or obesity related disorders (including peripheral vascular disease, cardiac failure, myocardial ischaemia, cerebral ischaemia, cardiac myopathies), diabetes, in particular type II diabetes mellitus, and/or complications arising therefrom (such as retinopathy, neuropathy, nephropathy), syndrome X, insulin resistance, impaired glucose tolerance, conditions of impaired fasting glucose, hypoglycemia, hyperglycemia, hyperuricemia, hyperinsulinemia, pancreatitis, hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed dyslipidemia, hypertriglyceridemia, nonalcoholic fatty liver disease, fatty liver, increased mesenteric fat, non-alcoholic steatohepatitis, liver fibrosis, metabolic acidosis, ketosis, dysmetabolic syndrome; dermatological conditions such as acne, psoriasis; cardiovascular diseases, such as atherosclerosis, arteriosclerosis, acute heart failure, congestive heart failure, coronary artery disease, cardiomyopathy, myocardial infarction, angina pectoris, hypertension, hypotension, stroke, ischemia, ischemic reperfusion injury, aneurysm, restenosis or vascular stenosis; neoplastic diseases, such as solid tumors, skin cancer, melanoma, lymphoma or endothelial cancers, e.g., breast cancer, lung cancer, colorectal cancer, stomach cancer, other cancers of the gastrointestinal tract (e.g., esophageal cancer and pancreatic cancer), prostate cancer, kidney cancer, liver cancer, bladder cancer, cervical cancer, uterine cancer, testicular cancer or ovarian cancer; or other diseases and conditions that are sensitive or responsive to modulation, in particular inhibition, of DGAT function, in particular DGAT1 function.

Particular diseases or disorders which can benefit from inhibition of DGAT, in particular DGAT1, are selected from obesity, hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed dyslipidemia, hypertriglyceridemia, fatty liver, nonalcoholic fatty liver disease, liver fibrosis, non-alcoholic steatohepatitis or diabetes, in particular type II diabetes.

The invention also relates to a compound of group Q for use in the prevention or the treatment, in particular for use in the treatment, of a disease or disorder which can benefit from inhibition of DGAT, in particular DGAT1.

In an embodiment the invention also relates to the use of a compound of group Q for the manufacture of a medicament for treating or preventing the above mentioned diseases or conditions.

In view of the DGAT inhibitory activity of the compounds of group Q, there is provided a method of treating a warm-blooded mammal, including a human, suffering from or a method of preventing a warm-blooded mammal, including a human, to suffer from a disease which can benefit from inhibition of DGAT, in particular a method of treating a warm-blooded mammal, including a human, suffering from a disease which can benefit from inhibition of DGAT. Said methods comprise the administration of an effective amount of a compound of group Q to a warm-blooded mammal, including a human.

In an embodiment, the present invention also relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier, and as active ingredient a therapeutically effective amount of a compound of group Q.

The present invention also provides compositions for preventing or treating a disease which can benefit from an elevated GLP-1 level or which can benefit from inhibition of DGAT, in particular DGAT1, in particular for treating a disease which can benefit from elevated GLP-1 levels or which can benefit from inhibition of DGAT, in particular DGAT1. Said compositions comprise a therapeutically effective amount of a compound of group Q and a pharmaceutically acceptable carrier.

The novel compounds of group Q of the present invention may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.

The compounds of group Q of the present invention may also be administered via inhalation or insufflation by means of methods and formulations employed in the art for administration via this way. Thus, in general the compounds of the present invention may be administered to the lungs in the form of a solution, a suspension or a dry powder. Any system developed for the delivery of solutions, suspensions or dry powders via oral or nasal inhalation or insufflation are suitable for the administration of the present compounds.

The compounds of the present invention may also be topically administered in the form of drops, in particular eye drops. Said eye drops may be in the form of a solution or a suspension. Any system developed for the delivery of solutions or suspensions as eye drops are suitable for the administration of the present compounds.

It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.

The exact dosage and frequency of administration depends on the particular compound of group Q used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention.

Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% by weight, more preferably from 0.1 to 70% by weight, even more preferably from 0.1 to 50% by weight of the compound of group Q, and, from 1 to 99.95% by weight, more preferably from 30 to 99.9% by weight, even more preferably from 50 to 99.9% by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.

The following examples are intended to illustrate the present invention.

EXPERIMENTAL PART

Hereinafter, the term ‘THF’ means tetrahydrofuran, ‘Et₂O’ means diethyl ether, ‘CH₃OH’ means methanol, ‘EtOAc’ means ethyl acetate, ‘NaHCO₃’ means carbonic acid monosodium salt, ‘CH₂Cl₂’ or ‘DCM’ means dichloromethane, ‘CH₃CN’ means acetonitrile, ‘EtOH’ means ethanol, ‘HBTU’ means 1-[bis(di-methylamino)methylene]-1H-benzo-triazoliumhexafluorophosphate(1-)3-oxide, ‘DMF’ means N,N-dimethyl-formamide, ‘DIPEA’ means N-ethyl-N-(1-methylethyl)-2-propanamine, ‘HOBt’ or ‘HOBT’ means 1-hydroxy-1H-benzotriazole, ‘EDCI’ means N-(ethylcarbonimidoyl)-NN-dimethyl-1,3-propanediamine monohydrochloride, ‘DMSO’ means dimethylsulfoxide, ‘m.p.’ means melting point, ‘MeOH’ means methanol, ‘Et₃N’ means triethylamine, ‘eq.’ means equivalent, ‘r.m.’ means reaction mixture, ‘Lt.’ means room temperature, ‘h’ means hour(s), ‘min’ means minute(s), and ‘TFA’ means trifluoroacetic acid.

Experimental Procedures for the Class A Compounds

The experimental procedures for the preparation of the compounds of Class A, are described in WO2008/148851, the content of which is enclosed by reference in the present application.

Experimental Procedures for the Class B Compounds

The experimental procedures for the preparation of the compounds of Class B, are described in WO2008/148840, the content of which is enclosed by reference in the present application.

Experimental Procedures for the Class C Compounds

The experimental procedures for the preparation of the compounds of Class C, are described in WO2008/148849, the content of which is enclosed by reference in the present application.

In addition, some typical examples of Class C compounds are described below.

Intermediates (Class C) Preparation of 4-(1-piperazinyl)-N-[3-(1-pyrrolidinyl)phenyl]-benzamide and 4-(1-piperazinyl)-N-[3-(1-pyrrolidinyl)phenyl]-benzamide .HCl

Pd/C 10% (1 g) was suspended in MeOH (150 ml) under N₂ flow. 4-[4-(phenylmethyl)-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide (5.62 g, 0.0126 mol; prepared according to the teachings described in WO2008/148849) was added and the r.m. was stirred at 50° C. under H₂ atmosphere until 1 eq. of H₂ was absorbed. The catalyst was filtered off over diatomaceous earth (DICALITE® (diatomaceous earth)). The solvent was evaporated and co-evaporated with toluene. The residue was stirred in Et₂O and filtered off. The product was dried (50° C., 18 h, in vacuo). Yield: 4.23 g of 4-(1-piperazinyl)-N-[3-(1-pyrrolidinyl)phenyl]-benzamide (96%).

4-(1-piperazinyl)-N-[3-(1-pyrrolidinyl)phenyl]-benzamide .HCl was prepared in analogy to the free base form. For the preparation of the hydrochloric acid salt, 4-[4-[[[3-(1-pyrrolidinyl)phenyl]amino]carbonyl]phenyl]-1-piperazinecarboxylic acid, 1,1-dimethylethyl ester (the tert-butoxy variant of 4-[4-(phenylmethyl)-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide) was deprotected with a HCl solution in dioxane.

Preparation of 1-[(4-bromo-3-chlorophenyl)methyl]-pyrrolidine

A solution of 1-bromo-2-chloro-4-(chloromethyl)-benzene (25.2 g, 105.03 mmol) and Et₃N (16.1 ml, 115.53 mmol) in THF (150 ml) was stirred at r.t. Pyrrolidine (8.2 g, 115.53 mmol) was added dropwise. The r.m. was stirred overnight at r.t. and was then concentrated in vacuo. The residue was taken up into water and extracted with CH₂Cl₂ (3×100 ml). The combined organic layer was washed with saturated NaHCO₃ and brine, and was then dried (MgSO₄), filtered and the solvent was evaporated in vacuo. Yield: 25.8 g of 1-[(4-bromo-3-chlorophenyl)methyl]-pyrrolidine (90% yield, crude product; used in next reaction step, without further purification).

Preparation of 2-chloro-4-(1-pyrrolidinylmethyl)-benzaldehyde

Reaction under N₂ atmosphere. A solution of 1-[(4-bromo-3-chlorophenyl)methyl]-pyrrolidine (25.8 g, 93.96 mmol) in THF (200 ml) was stirred at −78° C. for 15 min A 2.5 M n-BuLi solution in hexane was added to the mixture over a period of 15 min After 30 min, a solution of DMF (7.3 ml, 93.96 mmol) in THF (50 ml) was added dropwise to the mixture. The reaction temperature was allowed to rise to r.t. slowly, and the mixture was stirred overnight. The reaction was quenched by the addition of water at 0° C. The mixture was extracted with EtOAc (3×150 ml). The combined organic layer was washed with brine, dried (MgSO₄), filtered and the solvent was evaporated in vacuo.

Yield: 20.3 g of 2-chloro-4-(1-pyrrolidinylmethyl)-benzaldehyde (97%, crude Yield:). The crude product was used for next step directly without further purification.

Preparation of 2-chloro-α-hydroxy-4-(1-pyrrolidinylmethyl)-benzeneacetonitrile

Trimethylsilanecarbonitrile (10 ml, 76.6 mmol) and ZnBr₂ (0.5 g) were added to a solution of 2-chloro-4-(1-pyrrolidinylmethyl)-benzaldehyde (9.8 g, 43.8 mmol) in DCM (100 ml). The r.m. was stirred for 5 h at r.t. Then, the mixture was heated to 50° C. and stirred overnight. 2-chloro-α-hydroxy-4-(1-pyrrolidinylmethyl)-benzeneacetonitrile was used as a crude in the next reaction step.

Preparation of 2-chloro-α-hydroxy-4-(1-pyrrolidinylmethyl)-benzeneacetic acid (TFA-salt)

A mixture of 2-chloro-α-hydroxy-4-(1-pyrrolidinylmethyl)-benzeneacetonitrile (10.9 g, 43.8 mmol) in concentrated HCl (50 ml) was stirred and refluxed for 24 h. The mixture was cooled and the solvent was evaporated. The crude product was purified by preparative HPLC (Synergi: 250×20 mm; Mobile Phase: 0-30% CH₃CN in H₂O (0.1% TFA); Flow Rate: 80 ml/min; Finished Time: 30 min) The desired fraction was collected and the organic phase was evaporated to give a yellow oil. Yield: 6.2 g of 2-chloro-α-hydroxy-4-(1-pyrrolidinylmethyl)-benzeneacetic acid (TFA-salt), used as such in the next reaction step (52.5%; TFA-salt).

Final Compounds (Class C)

Preparation of Compound 152

A mixture of 2-chloro-α-hydroxy-4-(1-pyrrolidinylmethyl)-benzeneacetic acid (1.1 g, 2.87 mmol), 4-(1-piperazinyl)-N-[3-(1-pyrrolidinyl)phenyl]-benzamide .HCl (1.1 g, 2.87 mmol), EDCI (0.55 g, 2.87 mmol), HOBT (0.39 g, 2.87 mmol) and Et₃N (1.6 ml, 11.48 mmol) in DCM (50 ml) was stirred overnight at r.t. Water was added to the mixture, and the organic layer was separated. The aqueous layer was extracted with DCM (3×30 ml). The combined organic layer was washed with brine, dried (MgSO₄), filtered and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography over silica gel (eluent: DCM/MeOH 30/1). The product fractions were collected and the solvent was evaporated. Yield: 0.8 g of crude compound 152 (purity 82% on LCMS). The crude compound 152 was purified by neutral high performance liquid chromatography (Column: Daisopak 250×20 mm; Mobile Phase: 80-100% CH₃CN in water; Flow Rate: 14 ml/min; Finished Time: 15 min). The desired fraction was collected and evaporated in vacuo. Yield: 0.4 g of compound 152 (23%).

Compound 151 was prepared by analogy to compound 152, but 2-chloro-4-(1-pyrrolidinylmethyl)-benzeneacetic acid (for which the synthesis protocol is described in detail in the experimental procedures for the Class D compounds) was used as starting material.

Compounds 147, 148, 149 and 150 were also prepared by analogy to compound 152, starting from the appropriate starting materials.

Experimental Procedures for the Class D Compounds

The experimental procedures for the preparation of the compounds of Class D, are described in WO2008/148868, the content of which is enclosed by reference in the present application.

In addition, some typical examples of Class D compounds are described below.

Intermediates (Class D) Preparation of 1-[[3-chloro-4-(2,2-dibromoethenyl)phenyl]methyl]-pyrrolidine

A mixture of 2-chloro-4-(1-pyrrolidinylmethyl)-benzaldehyde (prepared according to the teachings in WO2008/148868) (10.0 g, 44.70 mmol) and tetrabromomethane (22.2 g, 67.05 mmol) in DCM (300 ml) was stirred at 0° C. A solution of triphenylphosphine (35.2 g, 134.10 mmol) in DCM (500 ml) was added. The mixture was stirred for 30 min at 0° C. The mixture was concentrated in vacuo. The residue was taken up into CHCl₃, and the precipitate was filtered off. The filtrate was concentrated in vacuo. The residue (crude 1-[[3-chloro-4-(2,2-dibromoethenyl)phenyl]methyl]-pyrrolidine) was used as such in the next reaction step.

Preparation of 1-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-pyrrolidine

A mixture of pyrrolidine (150 ml) and water (15 ml) was stirred at r.t. 1-[[3-chloro-4-(2,2-dibromoethenyl)phenyl]methyl]-pyrrolidine (crude, max. 44.70 mmol) was added to the mixture and subsequently, the mixture was stirred overnight at r.t. The solvent was evaporated, yielding 1-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-pyrrolidine as a crude that was used as such in the next reaction step.

Preparation of 2-chloro-4-(1-pyrrolidinylmethyl)-benzeneacetic acid

A solution of 1-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-pyrrolidine (crude, max. 44.70 mmol) in dioxane (100 ml) was stirred at r.t. A 6 M HCl solution was added. The mixture was stirred and refluxed for 3 days. The mixture was concentrated in vacuo. The residue was taken up in water and the mixture was brought to pH 10 with a 4 N NaOH solution. The solution was washed with diethyl ether (3×40 ml). The aqueous layer was acidified to pH 3 with a 6 N HCl solution. The mixture was concentrated in vacuo. The residue was purified by neutral high performance liquid chromatography (Column: Lana 300×50 mm, 10 μm; Mobile Phase: 0-20% CH₃CN in water; Flow Rate: 80 ml/min; Finished Time: 25 min). The desired fraction was collected and evaporated in vacuo. Yield: 2.8 g of 2-chloro-4-(1-pyrrolidinylmethyl)-benzeneacetic acid (25% yield over last 3 steps).

2,6-Dichloro-4-(1-pyrrolidinylmethyl)-benzeneacetyl chloride .HCl was prepared by analogy to 2-chloro-4-(1-pyrrolidinylmethyl)-benzeneacetic acid by using the appropriate reaction conditions well known to those skilled in the art.

2,6-Dichloro-4-(1-pyrrolidinylmethyl)-benzeneacetic acid .HCl was prepared by analogy to 2-chloro-4-(1-pyrrolidinylmethyl)-benzeneacetic acid by using the appropriate reaction conditions well known to those skilled in the art.

Preparation of 4-[4-[[[(3,5-dimethoxyphenyl)methyl]amino]carbonyl]phenyl]-1-piperazinecarboxylic acid, 1,1-dimethylethyl ester

A mixture of 3,5-dimethoxybenzenemethanamine (3.34 g, 20 mmol), 4-(4-carboxyphenyl)-1-piperazinecarboxylic acid, 1-(1,1-dimethylethyl) ester (6.13 g, 20 mmol), EDCI (4.2 g, 22 mmol), HOBT (2.97 g, 22 mmol), N(CH₂CH₃)₃ (12 ml) and DCM (80 ml) was stirred overnight at r.t. The solvent was evaporated. The residue was purified by column chromatography (eluent: petroleum ether/EtOAc 2/1). The desired fractions were collected and the solvent was evaporated. Yield: 5.3 g of 4-[4-[[[(3,5-dimethoxyphenyl)methyl]amino]carbonyl]phenyl]-1-piperazinecarboxylic acid, 1,1-dimethylethyl ester (58.24% yield).

Preparation of N-[(3,5-dimethoxyphenyl)methyl]-4-(1-piperazinyl)-benzamide (HCl-salt)

4-[4-[[[(3,5-dimethoxyphenyl)methyl]amino]carbonyl]phenyl]-1-piperazinecarboxylic acid, 1,1-dimethylethyl ester (5.2 g, 11.4 mmol) was dissolved in HCl/dioxane (100 ml) and the reaction solution was stirred overnight. The solvent was evaporated. The solid residue was washed with petroleum ether and dried. Yield: 4.2 g of N-[(3,5-dimethoxyphenyl)methyl]-4-(1-piperazinyl)-benzamide (HCl-salt) as a crude (97.7%). 1 g of the crude product was purified by preparative HPLC (YMC: 250×80 mm; Mobile Phase: 10-35% CH₃CN % in H₂O (0.1% TFA); Finished Time: 25 min) The desired fractions were collected and solvent was evaporated. The residue was neutralized with an aqueous NaHCO₃ solution and extracted with EtOAc. The separated organic layer was washed with brine, dried (Na₂SO₄), filtered and the solvent was evaporated to yield a white solid. Yield: 0.4 g of N-[(3,5-dimethoxyphenyl)methyl]-4-(1-piperazinyl)-benzamide (HCl-salt).

Final Compounds (Class D)

Preparation of Compound 353

A mixture of 2-chloro-4-(1-pyrrolidinylmethyl)-benzeneacetic acid (0.94 g, 3.70 mmol) and N-[(3,5-dimethoxyphenyl)methyl]-4-(1-piperazinyl)-benzamide (HCl-salt) (1.5 g, 3.83 mmol) in DCM (20 ml) was stirred at r.t. Et₃N (1.3 ml, 9.58 mmol) was added to the mixture. Then EDCI (0.73 g, 3.83 mmol) and HOBT (0.52 g, 3.83 mmol) were added to the mixture. The mixture was stirred overnight at r.t. The mixture was washed with water, dried (MgSO₄), filtered and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 20/1). The product fractions were collected and the solvent was evaporated. Yield: 0.78 g of compound 353 (36%).

Preparation of Compound 358

A mixture of 2,6-dichloro-4-(1-pyrrolidinylmethyl)-benzeneacetyl chloride .HCl and 2,6-dichloro-4-(1-pyrrolidinylmethyl)-benzeneacetic acid .HCl (1.29 g of the mixture) was added portionwise to a stirring mixture of N-[(3,5-dimethoxyphenyl)methyl]-4-(1-piperazinyl)-benzamide .HCl (1.406 g, 0.00358 mol) and NaHCO₃ (0.993 g, 0.0118 mol) in CH₃CN (60 ml; dried on molecular sieves). The r.m. was stirred under N₂ atmosphere for 4 h. Subsequently, Et₃N (1 ml) and HBTU (1.358 g, 0.00358 mol) were added and the r.m. was stirred at r.t. for 65 h. Then, the mixture was poured into stirring H₂O (300 ml) and this aqueous mixture was stirred for 20 min. The product was filtered off and washed with H₂O (3×). The product was stirred in boiling 2-propanol (70 ml), filtered off hot, and the filtrate was left standing for 3 h (crystallization started after 5 min) The product was filtered off, washed with 2-propanol (3×), and dried (50° C., in vacuo) to yield 1.12 g of compound 358 (50%). An additional amount of compound 358 (0.481 g) was obtained by evaporation of the filtrate and purification of the residue by HPLC. The desired fractions were evaporated and crystallized from boiling 2-propanol again.

Compounds 354, 355, 359, 360, 361, 362, 363 and 364 from Class D were prepared by analogy to compound 353, starting from the appropriate starting materials.

Compounds 356 and 357 from Class D were prepared by analogy to compounds 152 from Class C, starting from the appropriate starting materials.

The tables below list compounds of class A, class B, class C or class D. The novel compounds of group Q (compounds 147 till 152 from Class C and compounds 353 till 364 from Class D) are enclosed in class C and class D.

Table for the Class A Compounds

TABLE A1

Compound 8

Compound 10

Compound 11

Compound 12

Compound 13

Compound 14

Compound 15

Compound 16

Compound 17

Compound 18

Compound 19 Tables for the Class B Compounds

TABLE B1

Co. No. A X R¹ R^(q) 1 N

H— 2 N

H— 3 N

H— 4 N

H— 5 N

H— 6 N

H— 7 CH

H— 8 N

H— 9 N

H— 10 N

H— 11 N

H— 12 N

H— 13 N

H— 14 N

H— 15 N

H— 16 N

H— 17 N

H— 18 N

H— 19 N

H— 20 N

H— 21 N

H— 22 N

H— 23 N

H— 24 N

  mixture of RR and SS H— 25 N

H— 26 N

H— 27 N

H— 28 N

H— 29 N

H— 30 N

H— 31 N

H— 32 N

H— 33 N

H— 34 N

H— 35 N

H— 36 N

H— 37 N

H— 38 N

H— 39 N

H— 40 N

H— 41 N

H— 42 N

H— 43 N

H— 44 CH

H— 45 N

H— 46 CH

H— 47 N

H— 48 CH

H— 49 N

H— 50 CH

H— 51 N

H— 52 N

H— 53 N

54 N

55 N

56 N

57 N

HOCH₂— 58 N

59 N

HOCH₂— 60 N

61 N

HO— 62 N

HO— 63 N

64 N

65 N

TABLE B2

Co. No. X R¹ R² Salt 66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

trifluoroacetate salt 116

117

Tables for the Class C Compounds

TABLE C1

Comp. no. R^(1a) R^(1b) R^(1c) 125 H

H 12 H

H 13 H

H 4

H H 14 H

H 15 H H

16 H

H 17 H

H 18

H H 19 H H

20 H

H 21 H H

22

H H 23 H

H 24 H H

25 H H

26

H H 27 H H

28 H

H 29 H H

30 H H

31 H

H 32

H H 33 H H

34

H H 35

H H 36 H

H 127 H

H 37 H

H 38 H H

39

H H 40 H

H 41 H

H 42

H H 43 H

H 44 H H

45

H H 126 H H

TABLE C2

Comp. no. A R¹ Salt 46 CH

trifluoro- acetate 47 CH

trifluoro- acetate 48 CH

trifluoro- acetate 10 CH

trifluoro- acetate 49 CH

trifluoro- acetate 1 CH

50 CH

51 CH

52 CH

3 CH

53 CH

54 CH

55 CH

56 CH

57 CH

58 CH

59 CH

60 CH

61 CH

62 CH

63 CH

64 CH

11 N

2 N

65 N

66 N

67 N

TABLE C3

Co. no. X R² 6 —C═O

68 —NH—C═S

8 —NH—C═S

69 —NH—C═O (CH₃)₃—C— 5 —NH—C═O

70 —NH—C═O

71 —NH—C═O

72 —NH—C═O

73 —NH—C═O

74 —NH—C═O

75 —NH—C═O

76 —NH—C═O

77 —NH—C═O

78 —NH—C═O

79 —NH—C═O

80 —NH—C═O

81 —NH—C═O

82 —NH—C═O

83 —NH—C═O

84 —NH—C═O

85 —NH—C═O

86 —NH—C═O

87 —NH—C═O

88 —NH—C═O

89 —NH—C═O

90 —NH—C═O

91 —NH—C═O

92 —NH—C═O

93 —NH—C═O

94 —NH—C═O

9 —NH—C═O

95 —NH—C═O

96 —NH—C═O

97 —NH—C═O

98 —NH—C═O

99 —NH—C═O

100 —NH—C═O

101 —NH—C═O

102 —NH—C═O

103 —NH—C═O

104 —NH—C═O

105 —NH—C═O

106 —NH—C═O

TABLE C4

Co. no. R² 107 CH₂═CH—CH₂— 7

108

109

110

111

128

112

113

114

115

116

117

118

TABLE C5

Co. no. R² 119 CH₃—CH₂—CH₂— 120

121

122

123

124

TABLE C6

Comp. no. X R² R^(1a) R^(1a′) R^(1b) R^(1c) R⁷ 131 —CH₂—C═O

H H

H H 134 —CH₂—C═O

Cl Cl H H H 135 —CH₂—NH—C═O

Cl Cl H H H 133 —NH—C═O

H H H —OCH₃ F 130 —NH—C═O

H H

H H 147 —CH₂—C═O

H H

H H 148 —CH₂—C═O

H H

H H 149 —CH₂—C═O

H H

H H 150 —CH₂—C═O

H H

H H 151 —CH₂—C═O

H H

H H 152 —CH(OH)—C═O

H H

H H 129 —NH—C═O

H H

H H 132 —CH₂—C═O

H H

H H

TABLE C7

Comp. no. X R² R^(1a) R^(1b) R^(1c) 144 —NH—C═O

H H 142 —CH₂—C═O

H Br H 141 —CH₂—C═O

H H —(CH₂)₃CH₃ 139 —O—C═O

H

H 137 —NH—C═O

H

H 146 —CH₂—C═O

H

H 145 —CH₂—C═O

H

H 140 —NH—C═O

H

H 143 —NH—C═O

H

H 138 —NH—C═O

H

H 136 —NH—C═O

H

H Tables for the Class D Compounds

TABLE D1

R*, S* = relative stereochemistry Analytical Part

Analytical Data for the Compounds of Group Q (Compounds 147-152 from Class C and Compounds 353-364 from Class D):

LCMS

For (LC)MS-characterization of the compounds of the present invention, the following methods were used.

General Procedure A

The LCMS analyses for a number of compounds were done at the Surveyor MSQ™ (Thermo Finnigan, USA) comprising a photo diode array detector (PDA; 190-800 nm) and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector was configured with APCI (atmospheric pressure chemical ionization, + or − ions). Mass spectra were acquired by scanning from 45 to 1000 (of atomic mass unit) in 0.3 seconds. Typical APCI conditions use a corona discharge current of 10 μA and a cone voltage of 30 V. The APCI probe temperature was 640° C. Nitrogen was used as the nebulizer gas. Data acquisition was performed with an Xcalibur™ data system.

General Procedure B

The HPLC measurement was performed using an Agilent 1100 module comprising a pump, a diode-array detector (DAD) (wavelength used 220 nm), a column heater and a column as specified in the respective methods below. Flow from the column was split to a Agilent MSD Series G1946C and G1956A. MS detector was configured with API-ES (atmospheric pressure electrospray ionization). Mass spectra were acquired by scanning from 100 to 1000. The capillary needle voltage was 2500 V for positive ionization mode and 3000 V for negative ionization mode. Fragmentation voltage was 50 V. Drying gas temperature was maintained at 350° C. at a flow of 10 l/min.

Method 1

In addition to general procedure A: Reversed phase HPLC was carried out on a Waters XTerra MS C18 column (3.5 μm, 2.1×30 mm) with a flow rate of 1.0 ml/min Two mobile phases (mobile phase A: 0.1% aqueous solution of formic acid; mobile phase B: CH₃CN) were used. First, 100% A was hold for 0.1 minutes (min) Then a gradient was applied to 5% A and 95% B in 3 min and hold for 0.8 min. The injection volume was 1 μl. The column was at room temperature.

Method 2

In addition to general procedure B: Reversed phase HPLC was carried out on a YMC-Pack ODS-AQ, 50×2.0 mm 5 μm column with a flow rate of 0.8 ml/min. Two mobile phases (mobile phase A: water with 0.1% TFA; mobile phase B: CH₃CN with 0.05% TFA) were used. First, 90% A and 10% B was hold for 0.8 min. Then a gradient was applied to 20% A and 80% B in 3.7 min and hold for 3 min Typical injection volumes of 2 μl were used. Oven temperature was 50° C. (MS polarity: positive)

Method 3

In addition to general procedure B: Reversed phase HPLC was carried out on an Ultimate XB-C18, 50×2.1 mm 5 μm column with a flow rate of 0.8 ml/min Two mobile phases (mobile phase C: 10 mmol/L NH₄HCO₃; mobile phase D: CH₃CN) were used. First, 90% C and 10% D was hold for 0.8 min. Then a gradient was applied to 20% C and 80% D in 3.7 min and hold for 3 min. Typical injection volumes of 2 μl were used. Oven temperature was 50° C. (MS polarity: positive)

Method 4

In addition to general procedure B: Reversed phase HPLC was carried out on an Ultimate XB-C18, 50×2.1 mm 5 μm column with a flow rate of 0.8 ml/min Two mobile phases (mobile phase C: 10 mmol/L NH₄HCO₃; mobile phase D: CH₃CN) were used. First, 100% C was hold for 1 min. Then a gradient was applied to 40% C and 60% D in 4 min and hold for 2.5 min. Typical injection volumes of 2 μl were used. Oven temperature was 50° C. (MS polarity: positive)

Melting Points

For a number of compounds (147-150 of Class C; 358-364 of Class D), m.p. were determined by using a Gallenkamp apparatus from Sanyo Gallenkamp.

For a number of compounds (151-152 of Class C; 353-357 of Class D), m.p. were determined with a WRS-2A melting point apparatus that was purchased from Shanghai Precision and Scientific Instrument Co. Ltd. Melting points were measured with a linear heating up rate of 0.2-5.0° C./min. The reported values are melt ranges. The maximum temperature was 300° C.

TABLE Y (LC)MS analytical data and m.p. - R_(t) means retention time (in minutes); [MH]⁺ means the protonated mass of the compound (free base); Method refers to the method used for (LC)MS; ‘dec.’ means decomposition. Comp. Nr. R_(t) [MH]⁺ Method m.p. (° C.) 147 - Class C 1.62 620 1 262-263 148 - Class C 1.60 663 1 180-182 149 - Class C 1.63 677 1 250-252 150 - Class C 1.68 713 1 240-242 151 - Class C 3.41 586 2 224.1-225.4 152 - Class C 4.84 602 3 138.7-140.9 353 - Class D 3.49 591 2 126.6-128.1 354 - Class D 3.23 600 2 206.3-209.4 355 - Class D 3.42 561 2 153.3-155.2 356 - Class D 3.10 616 2 134.4-137.0 357 - Class D 5.65 607 4 dec. at 124.8 358 - Class D 1.57 625 1 199-200 359 - Class D 1.61 677 1 240-241 360 - Class D 1.52 668 1 159-160 361 - Class D 1.53 691 1 164-166 362 - Class D 1.51 682 1 123-126 363 - Class D 1.61 727 1 241-243 364 - Class D 1.56 718 1 152-154

Analytical data for the other Class A, Class B, Class C and Class D compounds are listed in WO2008/148851, WO2008/148840, WO2008/148849 and WO2008/148868, the contents of which are enclosed by reference in the present application.

Pharmacological Example

All mpk (mg/kg/day) values mentioned in the measurements described below, were estimated based on average food intake and average body weight.

A) Measurement of Inhibition of DGAT1 Activity by the Compounds of Class A, Class B, Class C and Class D

The inhibiting activity of compounds of Class A, Class B, Class C and Class D on DGAT1 activity was screened in a single well procedure assay using DGAT1 comprising membrane preparations and DGAT1 substrate comprising micelles and determining formed radio-active triacylglycerol coming in close proximity of a flashplate surface by radioluminescence.

Said assay is described in full detail in WO2006/067071, the content of which is incorporated herein by reference.

By DGAT1 activity is meant the transfer of coenzyme A activated fatty acids to the 3-position of 1,2-diacylglycerols, thus forming a triglyceride molecule, by enzyme DGAT1.

Step 1 of the Assay: Expression of DGAT1

human DGAT1 (NM012079.2) was cloned into the pFastBac vector, containing translation start, a FLAG-tag at the N-terminus as described in literature and a viral Kozak sequence (AAX) preceding the ATG to improve expression in insect cells. Expression was done as described in literature (Cases, S., Smith, S. J., Zheng, Y., Myers H. M., Lear, S. R., Sande, E., Novak, S., Collins, C., Welch, C. B., Lusis, A. J., Erickson, S. K. and Farese, R. V. (1998) Proc. Natl. Acad. Sci. USA 95, 13018-13023.) using SF9 cells.

Step 2 of the Assay: Preparation of DGAT1 Membranes

72 h transfected SF9 cells were collected by centrifugation (13000 rpm-15 min-4° C.) and lysed in 2×500 ml lysisbuffer (0.1M Sucrose, 50 mM KCl, 40 mM KH₂PO₄, 30 mM EDTA pH 7.2. Cells were homogenized by cell disruptor. After centrifugation 1380 rpm-15 min-4° C. (SN discarded), pellet was resuspended in 500 ml lysisbuffer and total cell membranes collected by ultracentrifugation at 34000 rpm (100 000 g) for 60 min (4° C.). The collected membranes were resuspended in lysis buffer, divided in aliquots and stored with 10% glycerol at −80° C. until use.

Step 3 of the Assay: Preparation of DGAT Substrate Comprising Micelles

Materials

-   a) 1,2-dioleoyl-sn-glycerol, 10 mg/ml (1,2-diacylglycerol (DAG))

Dissolve in acetonitrile; evaporate the acetonitrile solution under nitrogen and reconstitute in chloroform at a final concentration of 10 mg/ml.

-   b) L-α-phosphatidylcholine, 1 mg/ml (phosphatidylcholine (PC))     -   Dissolve in chloroform at a final concentration of 1 mg/ml and         store at 4° C. -   c) L-α-phosphatidyl-L-serine, 1 mg/ml (phophatidylserine (PS))     -   Dissolve in chloroform at a final concentration of 1 mg/ml and         store at 4° C.         Method

Add 1 ml dioleoyl-sn-glycerol (10 mg/ml) to 10 ml of L-α-phosphatidylcholine (1 mg/ml) and 10 ml of L-α-phosphatidyl-L-serine (1 mg/ml) in a thick glass recipient. Evaporate under nitrogen and put on ice for 15 min Reconstitute in 10 ml Tris/HCl (10 mM, pH 7.4) by sonication on ice. The sonification process includes sonification cycles of 10 seconds in the sonification bath followed by 10 seconds cool down on ice and repeating this sonification cycle till a homogeneous solution is obtained (takes about 15 min). The thus obtained micelles are stored at −20° C. till later use and contain DAG at a final concentration of 1.61 mM.

Step 4 of the Assay: DGAT FlashPlate™ Assay

Materials

-   a) Assaybuffer -   50 mM Tris-HCl (pH 7.4), 150 mM MgCl₂, 1 mM EDTA, 0.2% BSA. -   b) N-ethylmaleimide, 5M     -   Dissolve 5 g into a final volume of 8 ml DMSO 100% and store at         −20° C. in aliquots till later use. -   c) Substrate mix (for 1 384 well plate=3840 μl) -   612 μl micelles stock (51 μM final) -   16.6 μl oleoylCoA 9.7 mM -   23 μl [³H]-oleoylCoA (49 Ci/mmol, 500 μCi/ml) -   3188.4 μl Tris pH 7.4, 10 mM -   d) Enzyme mix (for 1 384 well plate=3520 μl) (5 μg/ml)     -   Add 11.73 μl of DGAT membrane stock (1500 μg/ml stock) to 3508         μl assay buffer. -   e) Stop mix (for 1 384 well plate=7.68 ml) (250 mM)     -   Add 384 μl of N-ethylmaleimide (5M) to 3.456 ml DMSO 100%, and         further dilute 3.84 ml of said solution with 3.84 ml DMSO 10%.         Method

DGAT activity in membrane preparations was assayed in 50 mM Tris-HCl (pH 7.4), 150 mM MgCl₂, 1 mM EDTA and 0.2% BSA, containing 50 μM DAG, 32 μg/ml PC/PS and 8.4 μM [³H]-oleoylCoA (at a specific activity of 30 nCi/well) in a final volume of 50 μl in 384-well format using the red shifted Basic Image FlashPlate™ (Perkin Elmer Cat. No. SMP400).

In detail, 10 μl enzyme mix and 10 μl substrate mix were added to 30 μl of assay buffer, optionally in the presence of 1 μl DMSO (blank and controls) or 1 μl of the compound to be tested. This r.m. was incubated for 120 min at 37° C. and the enzymatic reaction stopped by adding 20 μl of the stop mix. The plates were sealed and the vesicles allowed to settle overnight at room temperature. Plates were centrifuged for 5 min at 1500 rpm and measured in Leadseeker.

Experiments with different concentrations of the test compound were performed and curves were calculated and drawn based on % CTRL_(min) (% of normalized control).

% CTRL_(min), was calculated according to equation 1, % CTRL_(min)=(sample−LC)/(HC−LC)  Equation 1 where HC (high control) refers to the median of radioluminescence value measured in the wells with enzyme and substrate but without test compound, LC (low control) refers to median background radioluminescence value measured in the wells with substrate without enzyme and without test compound, and sample refers to the radioluminescence value measured in the wells with substrate, enzyme and test compound at a particular concentration.

The calculated % CTRL_(min) values form a sigmoidal dose response descending curve and from this curve pIC₅₀ values were calculated (−logIC₅₀ where IC₅₀ represents the concentration at which the test compound gives 50% inhibition of DGAT1 activity). All the tested compounds of Class A, C and D showed pIC₅₀ values between 5 and 9. All the tested compounds of Class B showed pIC₅₀ values between 5 and 8.5.

In order to determine selectivity of the present compounds for DGAT1 compared to DGAT2, the inhibiting activity of the compounds on DGAT2 was also determined in the above assay, slightly modified to obtain optimal assay conditions for DGAT2. The tested compounds did not show inhibiting activity for DGAT2 (Human DGAT2 (NM032564) was cloned and expressed as described in J. Biolog. Chem. 276(42), pp 38870-38876 (2001)).

For a selected number of compounds, the pIC50 values are shown in Table E.

TABLE E pIC₅₀ values Co. Nr. pIC₅₀ 151 - 6.50 Class C 152 - 7.45 Class C 147 - 7.41 Class C 148 - 8.04 Class C 149 - 8.21 Class C 150 - 8.22 Class C 353 - 6.59 Class D 354 - 6.19 Class D 355 - 6.04 Class D 356 - 7.13 Class D 357 - 7.26 Class D 358 - 7.59 Class D 359 - 7.55 Class D 360 - 8.12 Class D 361 - 7.87 Class D 362 - 8.04 Class D 363 - 7.94 Class D 364 - 8.24 Class D 352 - 6.45 Class D 351 - 6.62 Class D 267 - 6.97 Class D

Pharmacological data for the other Class A, Class B, Class C and Class D compounds are listed in WO2008/148851, WO2008/148840, WO2008/148849 and WO2008/148868, the contents of which are enclosed by reference in the present application.

B) In vivo Study for Effect of Test Compound on GLP-1 Plasma Levels

Elevation of GLP-1 plasma levels by a DGAT inhibitor can be studied as follows:

Dogs are deprived from food for a period of 22 h. At time 0, animals are given a liquid meal, containing 18% fat (w/w), by gavage with a stomach tube. The test compound is given orally together with the meal. Afterwards, a postprandial plasma profile is determined for GLP-1. Therefore, blood is collected at predetermined time intervals in ice-cooled Vacutainers EDTA-plasma tubes and GLP-1 levels are measured in the samples taken at 0 h (just before the meal) and at 0.5, 1, 2, 4, 6, 8 and 24 h after dosing. Six dogs (3 males and 3 females) are included per dosage group and the plasma GLP-1 profile is compared with their own GLP-1 profile previously determined in the same conditions but without administration of the test compound. GLP-1 determinations in plasma are performed with a Glucagon-like peptide-1 (active) ELISA kit 96-well plate of LINCO Research.

C) Food Intake/Body Weight Effect of DGAT/Fenofibrate Combination

General Procedure

Male C57BL/6 mice were housed in individually ventilated cages under controlled temperature (21° C.), humidity (45-65%) and light (12 h-12 h reverse light/dark cycle; Lights on—6 PM-6 AM). Mice were set on 60 kcal % fat energy diet until their average body weight was over 45 grams, at which time they were switched to a 45 kcal % fat diet.

For the purpose of Tests A, B and C, the mice were moved into modified type-2 cages with: doublewide food cup, wire grids and a tissue for bedding for several months before experiment to adapt to new housing/feeding conditions. Food (Research diets 45 kcal % diet D12451—see Scheme A) was provided in powdered form in a food hopper located off the front of the cage. Mice had been used to test several compounds for effects on food intake before being used in the current experiment, but had a wash-out period of at least one month before starting the current experiments.

Scheme A: Composition of control diet (high-fat) and premix (used for adding drug) Control Diet Added during D12451 Premix diet preparation Ingredient g/kg diet D04071407px g/kg diet Casein, 80 Mesh 233.1 233.1 L-Cystine 3.5 3.5 Corn Starch 84.8 84.8 Maltodextrin 10 3.5 3.5 Sucrose 201.4 201.4 Cellulose 58.3 58.3 Soybean Oil 29.1 29.1 Lard 206.8 104.9 102 Mineral Mix S10026 11.7 11.7 DiCalcium Phosphate 15.1 15.1 Calcium Carbonate 6.4 6.4 Potassium Citrate, 1 H20 19.2 19.2 Vitamin Mix 11.7 11.7 Choline Bitartrate 2.3 2.3 FD&C Red Dye #40 0.1

Compound 223 of Class D (Tests A and B) or compound 358 (Test C) of Class D, and/or fenofibrate (also called ‘F’ in the continuation of the pharmacological examples) were brought to a fine emulsion by stirring in the appropriate amount of soybean oil for 1 day. This was then mixed with the diet premix (Scheme A). The diet premix was formulated to contain none of the necessary soybean oil, and only half the final amount of lard. The soybean oil, and the rest of the lard was added in-house during diet preparation. After the soybean oil/drug was mixed with the premix for 15 min, the remainder of the lard was added to complete the diet. Diet was provided in powder form.

The mice were weighted the day before trial onset. For treatment allocation, mice were ranked according to body weight and randomly assigned to treatments within repetitions/blocks (40 mice, 4 treatments, 10 repetitions/block, unless otherwise mentioned). The food intake the day before trial onset was also measured.

At trial onset, mice's food (diet D12451) was replaced with the ‘inhouse’ diet made from premix D04071407px and added oil/lard, fenofibrate and/or the DGAT inhibitor. In tests A and B compound 223 of Class D (also called ‘D’ in the continuation of the pharmacological examples) was used:

Food cups were filled and weighted daily during the experiment. Body weight was recorded every 2^(nd) or 3^(rd) day.

Food Intake and Body Weight data were analyzed using General Linear Models procedures appropriate for a 2×2 factorial design with blocking and repeated measures. Means comparisons were done using Duncan's Multiple Range test (SAS For Windows, Version 8.02; SAS®, Cary, N.C.). Results were expressed as means±SEM (standard error of the mean).

Test A

In test A, the efficacy of the treatment in DIO C57BL/6 mice with only fenofibrate and only a DGAT inhibitor (compound 223 from Class D) was compared with the combined treatment with both D and fenofibrate.

For the purpose of test A, the mice were assigned to one of the following treatments:

-   -   45 kcal % fat diet (Control)     -   45 kcal % fat diet+0.05% fenofibrate (F)     -   45 kcal % fat diet+0.04% compound 223 from Class D (D)     -   45 kcal % fat diet+0.04% compound 223 from Class D+0.05%         fenofibrate (D+F)

The results of test A are shown in FIGS. A1 and A2.

In FIG. A1 it can be seen that except for 1 or 2 days out of the 12 day trial, food intake of mice fed with the compound 223 of Class D (D) or fenofibrate-containing (F) diet was not significantly less than control mice. In contrast, food intake of mice fed with the compound 223 of Class D and fenofibrate-containing (D+F) diet was significantly less (P<0.05) on 9 out of 12 days. The cumulative food intake of the compound 223 of Class D group (D) and the fenofibrate group (F) was not significantly less than the control group when compared by Duncans Multiple Range test (3.2% and 7.5% respectively); whereas food intake of the group with the compound 223 of Class D and fenofibrate-containing (D+F) diet was significantly less (23%) than all other groups (P<0.05). When cumulative intake was analysed as a 2×2 factorial design, there was a significant DGAT effect and fenofibrate effect (P<0.005), but there was also a significant DGAT (compound 223 from Class D) x fenofibrate interaction, indicating that the combined effect was larger than the main effect of either alone (P<0.05) (synergistic effect).

The average daily drug intake of mice fed with the compound 223 of Class D or fenofibrate-containing diet was 23.5 and 29 mpk/d respectively. The average daily drug intake of mice fed the compound 223 of Class D and fenofibrate-combination diet was 43.2 mg/kg/day.

In FIG. A2 it can be seen that by day 2, body weight loss of mice fed with the compound 223 of Class D and fenofibrate-containing diet was significantly greater than control mice (P<0.05). By day 4, body weight change of all drug treated mice was significantly different than controls. Mice fed with the compound 223 of Class D or fenofibrate-containing diet lost from 1-2 grams during the trial, whereas controls gained 0.6 grams. In contrast, mice fed with the compound 223 of Class D and fenofibrate-combination diet (D+F) significantly lost more weight than mice fed with either drug alone, indicating a synergistic effect of the 2 compounds on weight loss. When day 12 weight loss was analysed by a 2×2 factorial design, the main effect of DGAT and fenofibrate were both significant (P<0.001), but DGAT x fenofibrate interaction was also significant (type 3 SS, P<0.05). This test supports the increased effect on weight loss of the combination diet when compared with single treatment.

At the end of test A, blood was collected under isoflurane anesthesia for serum biochemistry determinations. There was no indication of enhanced liver enzymes with the combination diet. Blood glucose and serum triglyceride levels were consistently lower in the (D+F) diet group than the control group.

Test B

In test B, the efficacy of the treatment in DIO C57BL/6 mice with the fenofibrate/compound 223 from Class D combination was compared at different doses. In test A, fenofibrate and compound 223 of Class D were included at 0.05 and 0.04% of the diet (w/w) respectively. In test B, fenofibrate (F)/compound 223 of Class D (D) was included at 3 lower doses 0.05F/0.02D, 0.025F/0.02D and 0.0125F/0.01D.

For the purpose of test B, the mice were assigned to one of the following treatments:

-   -   45 kcal % fat diet (Control)     -   45 kcal % fat diet+0.02% D+0.05% F (0.05F/0.02D)     -   45 kcal % fat diet+0.02% D+0.025% F (0.025F/0.02D)     -   45 kcal % fat diet+0.01% D+0.0125% F (0.0125F/0.01D)

The results of test B are shown in FIGS. B1, B2 and B3.

The average daily drug intake of F/D was 26.0/10.4, 13.2/10.6 and 6.6/5.3 mpk/d respectively for mice fed with the high, medium and low concentration diets. In FIG. B1, it can be seen that the baseline food intake (i.e. day 0) of mice fed the 0.0125/0.01 was significantly lower than for other groups. During the first day of exposure to the drug-containing diets, all treatment groups ate significantly less than controls. (2.6 vs. 3.7 g for treated vs. controls respectively). Treated mice ate significantly (P<0.05 or less) less than controls on all trial days except days 9, 14 and 15.

In FIG. B2, it can be seen that body weight change of mice fed with F/D-containing diets was significantly different from control mice by the 2^(nd) day of the trial (all P<0.001). Body weight changed significantly over time (time effect, P<0.001), and was significantly influenced by treatment (time x treatment interaction (P<0.05).

In FIG. B3, food intake of all treatment groups on day 1 is shown. All groups ate about 30% less than controls regardless of dietary D/F combination.

It can be concluded that compound 223 of Class D in combination with fenofibrate, reduced food intake in diet-induced obese mice for almost 2 weeks. This reduction in food intake was accompanied with a significant weight change when compared to controls. Control mice gained almost 2 grams during the first 5 days of the experiment. It appeared that mice had lost some weight during adaptation to the feeding cages. Although they regained most of this weight prior to the trial, some control mice clearly still regained weight during the first week of the experiment. This was not the case for mice treated with the combination of compound 223 of Class D and fenofibrate, even when the 2 were combined in the diet at 0.01 and 0.0125% w/w respectively. These results suggest that fenofibrates may reduce the efficacious dose of a DGAT inhibitor and prolong the time a DGAT inhibitor will reduce food intake.

Test C

In test C, the efficacies of the treatments in DIO C57BL/6 mice with only fenofibrate and only a DGAT inhibitor (compound 358 from Class D) were compared with the combined treatment with both compound 358 of Class D and fenofibrate.

For the purpose of test C, the 32 DIO mice (n=8/group, average starting weight 46.5 g) were assigned to one of the following treatments:

-   -   45 kcal % fat diet (Control)     -   45 kcal % fat diet+0.05% fenofibrate (F)     -   45 kcal % fat diet+0.04% compound 358 from Class D     -   45 kcal % fat diet+0.04% compound 358 from Class D+0.05%         fenofibrate (F)

The results of test C are shown in FIGS. C1 and C2.

In FIG. C1 it can be seen that food intake of mice fed with a diet containing only compound 358 of Class D or a diet only containing fenofibrate, was not significantly less than control mice. Food intake of mice fed with the compound 358 of Class D+fenofibrate-containing diet was only significantly less (P<0.05) from controls on days 1 to 3, due to an increase in food intake above baseline levels in control mice rather than a decrease in intake of compound 358+fenofibrate-treated mice. The 21-day cumulative food intake of all drug-treated mice turned out not to be significantly less than the control group, although there was a tendency for mice fed compound 358 of Class D and fenofibrate-containing diet to eat less.

The average daily drug intake of mice fed with the compound 358 of Class D or fenofibrate-containing diet was 27 and 34 mpk/d respectively. The average daily drug intake of mice fed the compound 358 of Class D and fenofibrate-combination diet was 58 mg/kg/day.

When analysed as a 2×2 factorial experiment (FIG. C2), both DGAT and fenofibrate treated mice gained less weight than controls (21 days body weight change, both main effects P<0.05). The combination of the 2 treatments resulted in a weight loss corresponding to the additive effect of both (interaction P>0.05, no synergistic effect).

D) Short-term Food Intake Effect of DGAT/Fenofibrate Combination in Lean C57BL/6 Mice.

In Test A and Test B, it was demonstrated that DGAT inhibition (compound 223 of Class D, also called ‘D’) in combination with fenofibrate (F) significantly reduced food intake and body weight of diet-induced obese mice fed a high-fat diet to a greater degree than when either compound was administered alone. To further evaluate the mechanism of action of this food intake reduction, it was evaluated whether combined treatment with a DGAT inhibitor (compound 223 of Class D) and fenofibrate reduce food intake in mice fed with a low-fat diet.

For the experiment, animals were moved into modified type-2 cages as described before. Once in the feeding cages, mice were adapted to a 10 kcal % fat diet for 1 week before trial 1 was started.

For the purpose of this test, the mice were assigned to one of the following treatments:

-   -   Low Fat Diets (Trial 1; FIG. D1):     -   10 kcal % fat diet (Control)     -   10 kcal % fat diet+0.01% D+0.0125% F (0.01% D/0.0125% F)     -   10 kcal % fat diet+0.04% D+0.05% F (0.04% D/0.05% F)

High Fat Diet (Trial 2; FIG. D2)

-   -   45 kcal % fat diet (Control)     -   45 kcal % fat diet+0.01% D+0.0125% F (0.01% D/0.0125% F)     -   45 kcal % fat diet+0.02% D+0.05% F (0.02% D/0.05% F)

Compound 223 of Class D (D) and fenofibrate (F) were brought to a fine emulsion by stirring in the appropriate amount of soybean oil for 1 day. This was then mixed with the diet premix. After the soybean oil/drug was mixed with the premix for 15 min, the necessary amount of the lard was added to complete the diet. Diet was provided in powder form.

Mice's ‘baseline’ (BL) food intake was measured for 1 day before both Trial 1 (low-fat diet) and 2 (high-fat diet). For treatment allocation, mice were ranked according to their pretrial food intake and randomly assigned to treatments within repetitions/block (30 mice, 3 treatments, 8-9 repetitions/block). Several mice had low or high food intakes and were not included in the experiment.

Food intake data were analysed using General Linear Models procedures appropriate for a randomized complete block design. Means comparisons were done using Duncan's Multiple Range test (SAS For Windows, Version 8.02; SAS®, Cary, N.C.). Results are expressed as means±SEM.

Trial 1: Food Intake of Lean Mice Fed a Low-fat Diet

Mice were given 1 week to adapt to the food intake cages and a low-fat powdered diet (Research Diets D12450B—10 kcal % fat). After 1 day of baseline food intake measurement, mice's food was replaced by the same 10 kcal % fat diet containing 0/0, 0.01/0.0125 or 0.04/0.05% w/w D/F. The food cups were filled and weight daily during the 3-day experiment.

In FIG. D1 (Trial 1), it can be seen that food intake of mice fed the diet containing a 0.01/0.0125 D/F was not reduced at any time during the 3-day trial, whereas mice fed the diet containing 0.04/0.05 D/F reduced their food intake by 9% on day 1, but ate similar amounts as controls thereafter.

The average daily drug intake of F/D was 71/57 or 17/14 mpk/d respectively for mice fed the high, and low concentration diets.

Trial 2: Food Intake of Lean Mice Fed a High-fat Diet

At the termination of trial 1, mice were switched to a high-fat diet (D12451—45 kcal % fat) and allowed to adapt for 3 days. Once adapted, food intake was recorded for 1 day to establish a baseline food intake (for treatment allotment). The following day, mice were switched to the same 45 kcal % fat diet containing 0/0, 0.01/0.0125 or 0.02/0.05% w/w D/F (FIG. D2).

In FIG. D2, it is shown that food intake of mice fed the diets containing a 0.01/0.0125% and 0.02/0.05% D/F was significantly reduced compared to controls, especially on day 1. Thereafter lean mice adapted more quickly than was generally been observed with obese mice. By day 2, mice were eating 90% of control values.

The average daily drug intake of F/D was 44/18 or 10.8/8.6 mpk/d respectively for mice fed the high, and low concentration diets.

It can be seen from FIG. D3 that food intake during the first 24 h of exposure to the drug-supplemented diet (0.01% D/0.0125% F) was significantly reduced in mice fed a high-fat diet (24% below control levels), but not in mice fed a low-fat diet (4% below control levels). These results clearly indicate that a certain amount of dietary fat is necessary for the feeding suppressive effects of D/F.

E) Composition Examples

“Active ingredient” (a.i.) as used throughout these examples relates to, unless otherwise is indicated,

-   a) a combination of a DGAT inhibitor and a PPAR agonist or a prodrug     thereof; in particular to any one of the exemplified DGAT inhibitors     combined with a fibrate; or -   b) a compound of group Q.

Typical examples of recipes for the formulation of the invention are as follows:

1. Tablets

Active ingredient 5 to 100 mg Di-calcium phosphate 20 mg Lactose 30 mg Talcum 10 mg Magnesium stearate 5 mg Potato starch ad 200 mg

In addition to tablets wherein both the DGAT inhibitor and the PPAR agonist are comprised together in 1 tablet, the DGAT inhibitor and the PPAR agonist may also be present in separate tablets. In that case, the active ingredient will be the DGAT inhibitor for one tablet and the PPAR agonist for the second tablet.

2. Suspension

An aqueous suspension is prepared for oral administration so that each milliliter contains 1 to 5 mg of active ingredient, 50 mg of sodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg of sorbitol and water ad 1 ml.

3. Injectable

A parenteral composition is prepared by stirring 1.5% (weight/volume) of active ingredient in 0.9% NaCl solution.

4. Ointment

Active ingredient 5 to 1000 mg Stearyl alcohol 3 g Lanoline 5 g White petroleum 15 g Water ad 100 g 

The invention claimed is:
 1. A compound including any stereochemically isomeric form thereof, wherein the compound is selected from N-[4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]phenyl]-4-methoxy-benzeneacetamide; 4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide; 4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide; 4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide; 4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide; 4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide; 4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide; 4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide; 4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide; 4-[4-[[2,6-dichloro-4-[(4-ethyl-1-piperazinyl)methyl]phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide; 4-[4-[[2,6-dichloro-4-[(4-ethyl-1-piperazinyl)methyl]phenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide; 4-[4-[[2,6-dichloro-4-[[4-(methylsulfonyl)-1-piperazinyl]methyl]phenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide; 4-[4-[[4-[(4-acetyl-1-piperazinyl)methyl]-2,6-dichlorophenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide; 4-[4-[[2,6-dichloro-4-[[4-(methylsulfonyl)-1-piperazinyl]methyl]phenyl]acetyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide; 4-[4-[[4-[(4-acetyl-1-piperazinyl)methyl]-2,6-dichlorophenyl]acetyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide; 4-[4-[[2,6-dichloro-4-[[4-(methylsulfonyl)-1-piperazinyl]methyl]phenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide; 4-[4-[[4-[(4-acetyl-1-piperazinyl)methyl]-2,6-dichlorophenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide; 4-[4-[[2,6-dichloro-4-[(4-ethyl-1-piperazinyl)methyl]phenyl]acetyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide; a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.
 2. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim
 1. 